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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 李宣書 | zh_TW |
dc.contributor.advisor | Hsuan-Shu Lee | en |
dc.contributor.author | 楊士鋒 | zh_TW |
dc.contributor.author | Shih-Feng Yang | en |
dc.date.accessioned | 2023-08-09T16:21:17Z | - |
dc.date.available | 2023-11-09 | - |
dc.date.copyright | 2023-08-09 | - |
dc.date.issued | 2023 | - |
dc.date.submitted | 2023-07-21 | - |
dc.identifier.citation | [1] W.H.O. International Agency for Research on Cancer, Cancer today.
[2] A. Villanueva, Hepatocellular Carcinoma, N Engl J Med, 380 (2019) 1450-1462. [3] R.X. Zhu, W.K. Seto, C.L. Lai, M.F. Yuen, Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region, Gut Liver, 10 (2016) 332-339. [4] J. Ferlay, M. Colombet, I. Soerjomataram, C. Mathers, D.M. Parkin, M. Pineros, A. Znaor, F. Bray, Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods, Int J Cancer, 144 (2019) 1941-1953. [5] R.P. Thylur, S.K. Roy, A. Shrivastava, T.A. LaVeist, S. Shankar, R.K. Srivastava, Assessment of risk factors, and racial and ethnic differences in hepatocellular carcinoma, JGH Open, 4 (2020) 351-359. [6] K.A. McGlynn, J.L. Petrick, W.T. London, Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability, Clin Liver Dis, 19 (2015) 223-238. [7] E. Sagnelli, M. Macera, A. Russo, N. Coppola, C. Sagnelli, Epidemiological and etiological variations in hepatocellular carcinoma, Infection, 48 (2020) 7-17. [8] J. Wands, Hepatocellular carcinoma and sex, N Engl J Med, 357 (2007) 1974-1976. [9] H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries, CA Cancer J Clin, 71 (2021) 209-249. [10] A. Jemal, E.M. Ward, C.J. Johnson, K.A. Cronin, J. Ma, A.B. Ryerson, A. Mariotto, A.J. Lake, R. Wilson, R.L. Sherman, Annual report to the nation on the status of cancer, 1975–2014, featuring survival, JNCI: Journal of the National Cancer Institute, 109 (2017) djx030. [11] 110年死因統計結果分析, (2022). [12] T. Kanda, T. Goto, Y. Hirotsu, M. Moriyama, M. Omata, Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review, Int J Mol Sci, 20 (2019). [13] A.J. Kovalic, G. Cholankeril, S.K. Satapathy, Nonalcoholic fatty liver disease and alcoholic liver disease: metabolic diseases with systemic manifestations, Transl Gastroenterol Hepatol, 4 (2019) 65. [14] e.e.e. European Association for the Study of the Liver. Electronic address, L. European Association for the Study of the, EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma, J Hepatol, 69 (2018) 182-236. [15] J.A. Marrero, L.M. Kulik, C.B. Sirlin, A.X. Zhu, R.S. Finn, M.M. Abecassis, L.R. Roberts, J.K. Heimbach, Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases, Hepatology, 68 (2018) 723-750. [16] J.D. Yang, P. Hainaut, G.J. Gores, A. Amadou, A. Plymoth, L.R. Roberts, A global view of hepatocellular carcinoma: trends, risk, prevention and management, Nat Rev Gastroenterol Hepatol, 16 (2019) 589-604. [17] A. Jindal, A. Thadi, K. Shailubhai, Hepatocellular Carcinoma: Etiology and Current and Future Drugs, J Clin Exp Hepatol, 9 (2019) 221-232. [18] M. Reig, A. Forner, J. Rimola, J. Ferrer-Fabrega, M. Burrel, A. Garcia-Criado, R.K. Kelley, P.R. Galle, V. Mazzaferro, R. Salem, B. Sangro, A.G. Singal, A. Vogel, J. Fuster, C. Ayuso, J. Bruix, BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update, J Hepatol, 76 (2022) 681-693. [19] J.M. Llovet, R.K. Kelley, A. Villanueva, A.G. Singal, E. Pikarsky, S. Roayaie, R. Lencioni, K. Koike, J. Zucman-Rossi, R.S. Finn, Hepatocellular carcinoma, Nat Rev Dis Primers, 7 (2021) 6. [20] N.M. Tunissiolli, M.M.U. Castanhole-Nunes, P.M. Biselli-Chicote, E.C. Pavarino, R.F. da Silva, R.C. da Silva, E.M. Goloni-Bertollo, Hepatocellular Carcinoma: a Comprehensive Review of Biomarkers, Clinical Aspects, and Therapy, Asian Pac J Cancer Prev, 18 (2017) 863-872. [21] V. Mazzaferro, E. Regalia, R. Doci, S. Andreola, A. Pulvirenti, F. Bozzetti, F. Montalto, M. Ammatuna, A. Morabito, L. Gennari, Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis, N Engl J Med, 334 (1996) 693-699. [22] B. Franssen, G. Jibara, P. Tabrizian, M.E. Schwartz, S. Roayaie, Actual 10-year survival following hepatectomy for hepatocellular carcinoma, HPB (Oxford), 16 (2014) 830-835. [23] J.M. Llovet, J. Bruix, Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival, Hepatology, 37 (2003) 429-442. [24] J.M. Llovet, M.I. Real, X. Montana, R. Planas, S. Coll, J. Aponte, C. Ayuso, M. Sala, J. Muchart, R. Sola, J. Rodes, J. Bruix, G. Barcelona Liver Cancer, Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial, Lancet, 359 (2002) 1734-1739. [25] C.M. Lo, H. Ngan, W.K. Tso, C.L. Liu, C.M. Lam, R.T. Poon, S.T. Fan, J. Wong, Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma, Hepatology, 35 (2002) 1164-1171. [26] J.K. Heimbach, L.M. Kulik, R.S. Finn, C.B. Sirlin, M.M. Abecassis, L.R. Roberts, A.X. Zhu, M.H. Murad, J.A. Marrero, AASLD guidelines for the treatment of hepatocellular carcinoma, Hepatology, 67 (2018) 358-380. [27] J.M. Llovet, T. De Baere, L. Kulik, P.K. Haber, T.F. Greten, T. Meyer, R. Lencioni, Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma, Nat Rev Gastroenterol Hepatol, 18 (2021) 293-313. [28] T. Meyer, R. Fox, Y.T. Ma, P.J. Ross, M.W. James, R. Sturgess, C. Stubbs, D.D. Stocken, L. Wall, A. Watkinson, N. Hacking, T.R.J. Evans, P. Collins, R.A. Hubner, D. Cunningham, J.N. Primrose, P.J. Johnson, D.H. Palmer, Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial, Lancet Gastroenterol Hepatol, 2 (2017) 565-575. [29] M. Ikeda, C. Morizane, M. Ueno, T. Okusaka, H. Ishii, J. Furuse, Chemotherapy for hepatocellular carcinoma: current status and future perspectives, Jpn J Clin Oncol, 48 (2018) 103-114. [30] S.M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, Y. Cao, J. Shujath, S. Gawlak, D. Eveleigh, B. Rowley, L. Liu, L. Adnane, M. Lynch, D. Auclair, I. Taylor, R. Gedrich, A. Voznesensky, B. Riedl, L.E. Post, G. Bollag, P.A. Trail, BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis, Cancer Res, 64 (2004) 7099-7109. [31] Y.S. Chang, J. Adnane, P.A. Trail, J. Levy, A. Henderson, D. Xue, E. Bortolon, M. Ichetovkin, C. Chen, A. McNabola, D. Wilkie, C.A. Carter, I.C. Taylor, M. Lynch, S. Wilhelm, Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models, Cancer Chemother Pharmacol, 59 (2007) 561-574. [32] J.M. Llovet, S. Ricci, V. Mazzaferro, P. Hilgard, E. Gane, J.F. Blanc, A.C. de Oliveira, A. Santoro, J.L. Raoul, A. Forner, M. Schwartz, C. Porta, S. Zeuzem, L. Bolondi, T.F. Greten, P.R. Galle, J.F. Seitz, I. Borbath, D. Haussinger, T. Giannaris, M. Shan, M. Moscovici, D. Voliotis, J. Bruix, S.I.S. Group, Sorafenib in advanced hepatocellular carcinoma, N Engl J Med, 359 (2008) 378-390. [33] A.L. Cheng, Y.K. Kang, Z. Chen, C.J. Tsao, S. Qin, J.S. Kim, R. Luo, J. Feng, S. Ye, T.S. Yang, J. Xu, Y. Sun, H. Liang, J. Liu, J. Wang, W.Y. Tak, H. Pan, K. Burock, J. Zou, D. Voliotis, Z. Guan, Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial, Lancet Oncol, 10 (2009) 25-34. [34] M. Kudo, R.S. Finn, S. Qin, K.H. Han, K. Ikeda, F. Piscaglia, A. Baron, J.W. Park, G. Han, J. Jassem, J.F. Blanc, A. Vogel, D. Komov, T.R.J. Evans, C. Lopez, C. Dutcus, M. Guo, K. Saito, S. Kraljevic, T. Tamai, M. Ren, A.L. Cheng, Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial, Lancet, 391 (2018) 1163-1173. [35] Y. Yamamoto, J. Matsui, T. Matsushima, H. Obaishi, K. Miyazaki, K. Nakamura, O. Tohyama, T. Semba, A. Yamaguchi, S.S. Hoshi, F. Mimura, T. Haneda, Y. Fukuda, J.I. Kamata, K. Takahashi, M. Matsukura, T. Wakabayashi, M. Asada, K.I. Nomoto, T. Watanabe, Z. Dezso, K. Yoshimatsu, Y. Funahashi, A. Tsuruoka, Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage, Vasc Cell, 6 (2014) 18. [36] J. Bruix, S. Qin, P. Merle, A. Granito, Y.H. Huang, G. Bodoky, M. Pracht, O. Yokosuka, O. Rosmorduc, V. Breder, R. Gerolami, G. Masi, P.J. Ross, T. Song, J.P. Bronowicki, I. Ollivier-Hourmand, M. Kudo, A.L. Cheng, J.M. Llovet, R.S. Finn, M.A. LeBerre, A. Baumhauer, G. Meinhardt, G. Han, R. Investigators, Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet, 389 (2017) 56-66. [37] G.K. Abou-Alfa, T. Meyer, A.L. Cheng, A.B. El-Khoueiry, L. Rimassa, B.Y. Ryoo, I. Cicin, P. Merle, Y. Chen, J.W. Park, J.F. Blanc, L. Bolondi, H.J. Klumpen, S.L. Chan, V. Zagonel, T. Pressiani, M.H. Ryu, A.P. Venook, C. Hessel, A.E. Borgman-Hagey, G. Schwab, R.K. Kelley, Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma, N Engl J Med, 379 (2018) 54-63. [38] A.X. Zhu, Y.K. Kang, C.J. Yen, R.S. Finn, P.R. Galle, J.M. Llovet, E. Assenat, G. Brandi, M. Pracht, H.Y. Lim, K.M. Rau, K. Motomura, I. Ohno, P. Merle, B. Daniele, D.B. Shin, G. Gerken, C. Borg, J.B. Hiriart, T. Okusaka, M. Morimoto, Y. Hsu, P.B. Abada, M. Kudo, R.-s. investigators, Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Oncol, 20 (2019) 282-296. [39] J.B. Swann, M.J. Smyth, Immune surveillance of tumors, J Clin Invest, 117 (2007) 1137-1146. [40] S.J. Oiseth, M.S. Aziz, Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead, Journal of cancer metastasis and treatment, 3 (2017) 250-261. [41] E.F. McCarthy, The toxins of William B. Coley and the treatment of bone and soft-tissue sarcomas, Iowa Orthop J, 26 (2006) 154-158. [42] W.K. Decker, A. Safdar, Bioimmunoadjuvants for the treatment of neoplastic and infectious disease: Coley's legacy revisited, Cytokine Growth Factor Rev, 20 (2009) 271-281. [43] W.K. Decker, R.F. da Silva, M.H. Sanabria, L.S. Angelo, F. Guimaraes, B.M. Burt, F. Kheradmand, S. Paust, Cancer Immunotherapy: Historical Perspective of a Clinical Revolution and Emerging Preclinical Animal Models, Front Immunol, 8 (2017) 829. [44] M. Burnet, Cancer—a biological approach: III. Viruses associated with neoplastic conditions. IV. Practical applications, British medical journal, 1 (1957) 841. [45] M.T. Chow, A. Moller, M.J. Smyth, Inflammation and immune surveillance in cancer, Semin Cancer Biol, 22 (2012) 23-32. [46] G.M. Halliday, A. Patel, M.J. Hunt, F.J. Tefany, R.S. Barnetson, Spontaneous regression of human melanoma/nonmelanoma skin cancer: association with infiltrating CD4+ T cells, World J Surg, 19 (1995) 352-358. [47] F. Galli, J.V. Aguilera, B. Palermo, S.N. Markovic, P. Nistico, A. Signore, Relevance of immune cell and tumor microenvironment imaging in the new era of immunotherapy, J Exp Clin Cancer Res, 39 (2020) 89. [48] J.M. Kirkwood, J.G. Ibrahim, V.K. Sondak, J. Richards, L.E. Flaherty, M.S. Ernstoff, T.J. Smith, U. Rao, M. Steele, R.H. Blum, High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190, J Clin Oncol, 18 (2000) 2444-2458. [49] A. Morales, D. Eidinger, A.W. Bruce, Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors, J Urol, 116 (1976) 180-183. [50] S.A. Rosenberg, J.C. Yang, S.L. Topalian, D.J. Schwartzentruber, J.S. Weber, D.R. Parkinson, C.A. Seipp, J.H. Einhorn, D.E. White, Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2, JAMA, 271 (1994) 907-913. [51] R.S. Finn, S. Qin, M. Ikeda, P.R. Galle, M. Ducreux, T.Y. Kim, M. Kudo, V. Breder, P. Merle, A.O. Kaseb, D. Li, W. Verret, D.Z. Xu, S. Hernandez, J. Liu, C. Huang, S. Mulla, Y. Wang, H.Y. Lim, A.X. Zhu, A.L. Cheng, I.M. Investigators, Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma, N Engl J Med, 382 (2020) 1894-1905. [52] G.K. Abou-Alfa, G. Lau, M. Kudo, S.L. Chan, R.K. Kelley, J. Furuse, W. Sukeepaisarnjaroen, Y.-K. Kang, T. Van Dao, E.N. De Toni, Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma, NEJM Evidence, 1 (2022) EVIDoa2100070. [53] C.R. Institute, Immunotherapy Treatment Types. [54] S. Farkona, E.P. Diamandis, I.M. Blasutig, Cancer immunotherapy: the beginning of the end of cancer?, BMC Med, 14 (2016) 73. [55] Y. Shiravand, F. Khodadadi, S.M.A. Kashani, S.R. Hosseini-Fard, S. Hosseini, H. Sadeghirad, R. Ladwa, K. O'Byrne, A. Kulasinghe, Immune Checkpoint Inhibitors in Cancer Therapy, Curr Oncol, 29 (2022) 3044-3060. [56] D.B. Johnson, C.A. Nebhan, J.J. Moslehi, J.M. Balko, Immune-checkpoint inhibitors: long-term implications of toxicity, Nat Rev Clin Oncol, 19 (2022) 254-267. [57] H. Li, P.A. van der Merwe, S. Sivakumar, Biomarkers of response to PD-1 pathway blockade, Br J Cancer, 126 (2022) 1663-1675. [58] Q. Lei, D. Wang, K. Sun, L. Wang, Y. Zhang, Resistance Mechanisms of Anti-PD1/PDL1 Therapy in Solid Tumors, Front Cell Dev Biol, 8 (2020) 672. [59] Y. Liu, P. Zheng, How Does an Anti-CTLA-4 Antibody Promote Cancer Immunity?, Trends Immunol, 39 (2018) 953-956. [60] P. Berraondo, M.F. Sanmamed, M.C. Ochoa, I. Etxeberria, M.A. Aznar, J.L. Perez-Gracia, M.E. Rodriguez-Ruiz, M. Ponz-Sarvise, E. Castanon, I. Melero, Cytokines in clinical cancer immunotherapy, Br J Cancer, 120 (2019) 6-15. [61] G. Stary, C. Bangert, M. Tauber, R. Strohal, T. Kopp, G. Stingl, Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells, J Exp Med, 204 (2007) 1441-1451. [62] J.C. Yang, S.A. Rosenberg, Adoptive T-Cell Therapy for Cancer, Adv Immunol, 130 (2016) 279-294. [63] E. Leon, R. Ranganathan, B. Savoldo, Adoptive T cell therapy: Boosting the immune system to fight cancer, Semin Immunol, 49 (2020) 101437. [64] M. Sabry, M.W. Lowdell, Killers at the crossroads: The use of innate immune cells in adoptive cellular therapy of cancer, Stem Cells Transl Med, 9 (2020) 974-984. [65] N.-N.C. INSTITUTE, CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers, 2022. [66] M. Morotti, A. Albukhari, A. Alsaadi, M. Artibani, J.D. Brenton, S.M. Curbishley, T. Dong, M.L. Dustin, Z. Hu, N. McGranahan, M.L. Miller, L. Santana-Gonzalez, L.W. Seymour, T. Shi, P. Van Loo, C. Yau, H. White, N. Wietek, D.N. Church, D.C. Wedge, A.A. Ahmed, Promises and challenges of adoptive T-cell therapies for solid tumours, Br J Cancer, 124 (2021) 1759-1776. [67] S.Z. Shalhout, D.M. Miller, K.S. Emerick, H.L. Kaufman, Therapy with oncolytic viruses: progress and challenges, Nat Rev Clin Oncol, 20 (2023) 160-177. [68] C.S. Ilkow, S.L. Swift, J.C. Bell, J.S. Diallo, From scourge to cure: tumour-selective viral pathogenesis as a new strategy against cancer, PLoS Pathog, 10 (2014) e1003836. [69] G.D. Cao, X.B. He, Q. Sun, S. Chen, K. Wan, X. Xu, X. Feng, P.P. Li, B. Chen, M.M. Xiong, The Oncolytic Virus in Cancer Diagnosis and Treatment, Front Oncol, 10 (2020) 1786. [70] G. Marelli, A. Howells, N.R. Lemoine, Y. Wang, Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer, Front Immunol, 9 (2018) 866. [71] A.M. Scott, J.P. Allison, J.D. Wolchok, Monoclonal antibodies in cancer therapy, Cancer Immun, 12 (2012) 14. [72] S. Saini, Y. Kumar, Bispecific antibodies: a promising entrant in cancer immunotherapy, Translational Biotechnology, Elsevier2021, pp. 233-266. [73] S. Jin, Y. Sun, X. Liang, X. Gu, J. Ning, Y. Xu, S. Chen, L. Pan, Emerging new therapeutic antibody derivatives for cancer treatment, Signal Transduct Target Ther, 7 (2022) 39. [74] M. Vanneman, G. Dranoff, Combining immunotherapy and targeted therapies in cancer treatment, Nat Rev Cancer, 12 (2012) 237-251. [75] L.M. Weiner, J.C. Murray, C.W. Shuptrine, Antibody-based immunotherapy of cancer, Cell, 148 (2012) 1081-1084. [76] T. Enokida, A. Moreira, N. Bhardwaj, Vaccines for immunoprevention of cancer, J Clin Invest, 131 (2021). [77] M. Saxena, S.H. van der Burg, C.J.M. Melief, N. Bhardwaj, Therapeutic cancer vaccines, Nat Rev Cancer, 21 (2021) 360-378. [78] M.H. Chang, Cancer prevention by vaccination against hepatitis B, Recent Results Cancer Res, 181 (2009) 85-94. [79] S. Shanmugasundaram, J. You, Targeting Persistent Human Papillomavirus Infection, Viruses, 9 (2017). [80] R. Zappasodi, T. Merghoub, J.D. Wolchok, Emerging Concepts for Immune Checkpoint Blockade-Based Combination Therapies, Cancer Cell, 33 (2018) 581-598. [81] M. Kudo, Immune Checkpoint Inhibition in Hepatocellular Carcinoma: Basics and Ongoing Clinical Trials, Oncology, 92 Suppl 1 (2017) 50-62. [82] A.B. El-Khoueiry, B. Sangro, T. Yau, T.S. Crocenzi, M. Kudo, C. Hsu, T.Y. Kim, S.P. Choo, J. Trojan, T.H.R. Welling, T. Meyer, Y.K. Kang, W. Yeo, A. Chopra, J. Anderson, C. Dela Cruz, L. Lang, J. Neely, H. Tang, H.B. Dastani, I. Melero, Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial, Lancet, 389 (2017) 2492-2502. [83] P. Sharma, J.P. Allison, The future of immune checkpoint therapy, Science, 348 (2015) 56-61. [84] A.X. Zhu, R.S. Finn, J. Edeline, S. Cattan, S. Ogasawara, D. Palmer, C. Verslype, V. Zagonel, L. Fartoux, A. Vogel, D. Sarker, G. Verset, S.L. Chan, J. Knox, B. Daniele, A.L. Webber, S.W. Ebbinghaus, J. Ma, A.B. Siegel, A.L. Cheng, M. Kudo, K.-. investigators, Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial, Lancet Oncol, 19 (2018) 940-952. [85] T. Yau, J. Park, R. Finn, A.-L. Cheng, P. Mathurin, J. Edeline, M. Kudo, K.-H. Han, J. Harding, P. Merle, CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC), Annals of Oncology, 30 (2019) v874-v875. [86] R.S. Finn, B.Y. Ryoo, P. Merle, M. Kudo, M. Bouattour, H.Y. Lim, V. Breder, J. Edeline, Y. Chao, S. Ogasawara, T. Yau, M. Garrido, S.L. Chan, J. Knox, B. Daniele, S.W. Ebbinghaus, E. Chen, A.B. Siegel, A.X. Zhu, A.L. Cheng, K.-. investigators, Pembrolizumab As Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial, J Clin Oncol, 38 (2020) 193-202. [87] P. Merle, J. Edeline, M. Bouattour, A.-L. Cheng, S.L. Chan, T. Yau, M. Garrido, J.J. Knox, B. Daniele, A.X. Zhu, V.V. Breder, H.Y. Lim, S. Ogasawara, A.B. Siegel, A. Rahman, Z. Wei, R.S. Finn, Pembrolizumab (pembro) vs placebo (pbo) in patients (pts) with advanced hepatocellular carcinoma (aHCC) previously treated with sorafenib: Updated data from the randomized, phase III KEYNOTE-240 study, Journal of Clinical Oncology, 39 (2021) 268-268. [88] J. Giraud, D. Chalopin, J.F. Blanc, M. Saleh, Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies, Front Immunol, 12 (2021) 655697. [89] F. Foerster, S.J. Gairing, S.I. Ilyas, P.R. Galle, Emerging immunotherapy for HCC: A guide for hepatologists, Hepatology, 75 (2022) 1604-1626. [90] J.D. Wolchok, V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J.J. Grob, C.L. Cowey, C.D. Lao, J. Wagstaff, D. Schadendorf, P.F. Ferrucci, M. Smylie, R. Dummer, A. Hill, D. Hogg, J. Haanen, M.S. Carlino, O. Bechter, M. Maio, I. Marquez-Rodas, M. Guidoboni, G. McArthur, C. Lebbe, P.A. Ascierto, G.V. Long, J. Cebon, J. Sosman, M.A. Postow, M.K. Callahan, D. Walker, L. Rollin, R. Bhore, F.S. Hodi, J. Larkin, Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma, N Engl J Med, 377 (2017) 1345-1356. [91] M.D. Hellmann, N.A. Rizvi, J.W. Goldman, S.N. Gettinger, H. Borghaei, J.R. Brahmer, N.E. Ready, D.E. Gerber, L.Q. Chow, R.A. Juergens, F.A. Shepherd, S.A. Laurie, W.J. Geese, S. Agrawal, T.C. Young, X. Li, S.J. Antonia, Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study, Lancet Oncol, 18 (2017) 31-41. [92] R.J. Motzer, N.M. Tannir, D.F. McDermott, O. Aren Frontera, B. Melichar, T.K. Choueiri, E.R. Plimack, P. Barthelemy, C. Porta, S. George, T. Powles, F. Donskov, V. Neiman, C.K. Kollmannsberger, P. Salman, H. Gurney, R. Hawkins, A. Ravaud, M.O. Grimm, S. Bracarda, C.H. Barrios, Y. Tomita, D. Castellano, B.I. Rini, A.C. Chen, S. Mekan, M.B. McHenry, M. Wind-Rotolo, J. Doan, P. Sharma, H.J. Hammers, B. Escudier, I. CheckMate, Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma, N Engl J Med, 378 (2018) 1277-1290. [93] M.J. Overman, S. Lonardi, K.Y.M. Wong, H.J. Lenz, F. Gelsomino, M. Aglietta, M.A. Morse, E. Van Cutsem, R. McDermott, A. Hill, M.B. Sawyer, A. Hendlisz, B. Neyns, M. Svrcek, R.A. Moss, J.M. Ledeine, Z.A. Cao, S. Kamble, S. Kopetz, T. Andre, Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer, J Clin Oncol, 36 (2018) 773-779. [94] T. Yau, Y.K. Kang, T.Y. Kim, A.B. El-Khoueiry, A. Santoro, B. Sangro, I. Melero, M. Kudo, M.M. Hou, A. Matilla, F. Tovoli, J.J. Knox, A. Ruth He, B.F. El-Rayes, M. Acosta-Rivera, H.Y. Lim, J. Neely, Y. Shen, T. Wisniewski, J. Anderson, C. Hsu, Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial, JAMA Oncol, 6 (2020) e204564. [95] A.B. El-Khoueiry, T. Yau, Y.-K. Kang, T.-Y. Kim, A. Santoro, B. Sangro, I. Melero, M. Kudo, M.-M. Hou, A. Matilla, F. Tovoli, J.J. Knox, A.R. He, B.F. El-Rayes, M. Acosta-Rivera, H.Y. Lim, A. Memaj, A.R. Sama, C. Hsu, Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (Pts) with advanced hepatocellular carcinoma (aHCC): Long-term results from CheckMate 040, Journal of Clinical Oncology, 39 (2021) 269-269. [96] U.S.F.D. ADMINISTRATION, FDA approves atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma, 2020. [97] R.S. Finn, S. Qin, M. Ikeda, P.R. Galle, M. Ducreux, T.-Y. Kim, H.Y. Lim, M. Kudo, V.V. Breder, P. Merle, A.O. Kaseb, D. Li, W. Verret, H. Shao, J. Liu, L. Li, A.X. Zhu, A.-L. Cheng, IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC), Journal of Clinical Oncology, 39 (2021) 267-267. [98] A.L. Cheng, C. Hsu, S.L. Chan, S.P. Choo, M. Kudo, Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma, J Hepatol, 72 (2020) 307-319. [99] P.A. Ott, F.S. Hodi, H.L. Kaufman, J.M. Wigginton, J.D. Wolchok, Combination immunotherapy: a road map, J Immunother Cancer, 5 (2017) 16. [100] T. Blankenstein, P.G. Coulie, E. Gilboa, E.M. Jaffee, The determinants of tumour immunogenicity, Nat Rev Cancer, 12 (2012) 307-313. [101] P.S. Hegde, V. Karanikas, S. Evers, The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition, Clin Cancer Res, 22 (2016) 1865-1874. [102] C.H. Shim, S. Cho, Y.M. Shin, J.M. Choi, Emerging role of bystander T cell activation in autoimmune diseases, BMB Rep, 55 (2022) 57-64. [103] J. Liu, M. Fu, M. Wang, D. Wan, Y. Wei, X. Wei, Cancer vaccines as promising immuno-therapeutics: platforms and current progress, J Hematol Oncol, 15 (2022) 28. [104] L. Miao, Y. Zhang, L. Huang, mRNA vaccine for cancer immunotherapy, Mol Cancer, 20 (2021) 41. [105] N.-N.C. INSTITUTE, What Is Cancer?, NIH-NATIONAL CANCER INSTITUTE, 2021. [106] A.A. Itano, S.J. McSorley, R.L. Reinhardt, B.D. Ehst, E. Ingulli, A.Y. Rudensky, M.K. Jenkins, Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity, Immunity, 19 (2003) 47-57. [107] M.A. West, R.P. Wallin, S.P. Matthews, H.G. Svensson, R. Zaru, H.G. Ljunggren, A.R. Prescott, C. Watts, Enhanced dendritic cell antigen capture via toll-like receptor-induced actin remodeling, Science, 305 (2004) 1153-1157. [108] F. Sallusto, M. Cella, C. Danieli, A. Lanzavecchia, Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products, J Exp Med, 182 (1995) 389-400. [109] J. Borst, T. Ahrends, N. Babala, C.J.M. Melief, W. Kastenmuller, CD4(+) T cell help in cancer immunology and immunotherapy, Nat Rev Immunol, 18 (2018) 635-647. [110] R. Forster, A. Schubel, D. Breitfeld, E. Kremmer, I. Renner-Muller, E. Wolf, M. Lipp, CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs, Cell, 99 (1999) 23-33. [111] S. Calabro, D. Liu, A. Gallman, M.S. Nascimento, Z. Yu, T.T. Zhang, P. Chen, B. Zhang, L. Xu, U. Gowthaman, J.K. Krishnaswamy, A.M. Haberman, A. Williams, S.C. Eisenbarth, Differential Intrasplenic Migration of Dendritic Cell Subsets Tailors Adaptive Immunity, Cell Rep, 16 (2016) 2472-2485. [112] M. Binnewies, A.M. Mujal, J.L. Pollack, A.J. Combes, E.A. Hardison, K.C. Barry, J. Tsui, M.K. Ruhland, K. Kersten, M.A. Abushawish, M. Spasic, J.P. Giurintano, V. Chan, A.I. Daud, P. Ha, C.J. Ye, E.W. Roberts, M.F. Krummel, Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4(+) T Cell Immunity, Cell, 177 (2019) 556-571 e516. [113] A. Brewitz, S. Eickhoff, S. Dahling, T. Quast, S. Bedoui, R.A. Kroczek, C. Kurts, N. Garbi, W. Barchet, M. Iannacone, F. Klauschen, W. Kolanus, T. Kaisho, M. Colonna, R.N. Germain, W. Kastenmuller, CD8(+) T Cells Orchestrate pDC-XCR1(+) Dendritic Cell Spatial and Functional Cooperativity to Optimize Priming, Immunity, 46 (2017) 205-219. [114] E.W. Roberts, M.L. Broz, M. Binnewies, M.B. Headley, A.E. Nelson, D.M. Wolf, T. Kaisho, D. Bogunovic, N. Bhardwaj, M.F. Krummel, Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma, Cancer Cell, 30 (2016) 324-336. [115] M.K. Ruhland, E.W. Roberts, E. Cai, A.M. Mujal, K. Marchuk, C. Beppler, D. Nam, N.K. Serwas, M. Binnewies, M.F. Krummel, Visualizing Synaptic Transfer of Tumor Antigens among Dendritic Cells, Cancer Cell, 37 (2020) 786-799 e785. [116] C.J. Melief, Mutation-specific T cells for immunotherapy of gliomas, N Engl J Med, 372 (2015) 1956-1958. [117] J. Zhou, S. Jiang, W. Wang, R. Liu, [Research Progress of Tumor-Associated Neutrophils and Lung Cancer], Zhongguo Fei Ai Za Zhi, 22 (2019) 727-731. [118] S. Halle, O. Halle, R. Forster, Mechanisms and Dynamics of T Cell-Mediated Cytotoxicity In Vivo, Trends Immunol, 38 (2017) 432-443. [119] D.A. Thomas, J. Massague, TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance, Cancer Cell, 8 (2005) 369-380. [120] D. Jorgovanovic, M. Song, L. Wang, Y. Zhang, Roles of IFN-gamma in tumor progression and regression: a review, Biomark Res, 8 (2020) 49. [121] R. Noubade, S. Majri-Morrison, K.V. Tarbell, Beyond cDC1: Emerging Roles of DC Crosstalk in Cancer Immunity, Front Immunol, 10 (2019) 1014. [122] J. Lee, B. Lozano-Ruiz, F.M. Yang, D.D. Fan, L. Shen, J.M. Gonzalez-Navajas, The Multifaceted Role of Th1, Th9, and Th17 Cells in Immune Checkpoint Inhibition Therapy, Front Immunol, 12 (2021) 625667. [123] O.A. Haabeth, K.B. Lorvik, C. Hammarstrom, I.M. Donaldson, G. Haraldsen, B. Bogen, A. Corthay, Inflammation driven by tumour-specific Th1 cells protects against B-cell cancer, Nat Commun, 2 (2011) 240. [124] C.M. Laumont, A.C. Banville, M. Gilardi, D.P. Hollern, B.H. Nelson, Tumour-infiltrating B cells: immunological mechanisms, clinical impact and therapeutic opportunities, Nat Rev Cancer, 22 (2022) 414-430. [125] N.R. Saeed Farajzadeh Valilou, Chapter 4 - Tumor Antigens, 2019. [126] P.G. Coulie, B.J. Van den Eynde, P. van der Bruggen, T. Boon, Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy, Nat Rev Cancer, 14 (2014) 135-146. [127] R.E. Hollingsworth, K. Jansen, Turning the corner on therapeutic cancer vaccines, NPJ Vaccines, 4 (2019) 7. [128] Z. Zhang, M. Lu, Y. Qin, W. Gao, L. Tao, W. Su, J. Zhong, Neoantigen: A New Breakthrough in Tumor Immunotherapy, Front Immunol, 12 (2021) 672356. [129] C. De Smet, C. Lurquin, P. van der Bruggen, E. De Plaen, F. Brasseur, T. Boon, Sequence and expression pattern of the human MAGE2 gene, Immunogenetics, 39 (1994) 121-129. [130] S. Gnjatic, E. Ritter, M.W. Buchler, N.A. Giese, B. Brors, C. Frei, A. Murray, N. Halama, I. Zornig, Y.T. Chen, C. Andrews, G. Ritter, L.J. Old, K. Odunsi, D. Jager, Seromic profiling of ovarian and pancreatic cancer, Proc Natl Acad Sci U S A, 107 (2010) 5088-5093. [131] O. Hofmann, O.L. Caballero, B.J. Stevenson, Y.T. Chen, T. Cohen, R. Chua, C.A. Maher, S. Panji, U. Schaefer, A. Kruger, M. Lehvaslaiho, P. Carninci, Y. Hayashizaki, C.V. Jongeneel, A.J. Simpson, L.J. Old, W. Hide, Genome-wide analysis of cancer/testis gene expression, Proc Natl Acad Sci U S A, 105 (2008) 20422-20427. [132] A.J. Simpson, O.L. Caballero, A. Jungbluth, Y.T. Chen, L.J. Old, Cancer/testis antigens, gametogenesis and cancer, Nat Rev Cancer, 5 (2005) 615-625. [133] J. Karbach, A. Neumann, A. Atmaca, C. Wahle, K. Brand, L. von Boehmer, A. Knuth, A. Bender, G. Ritter, L.J. Old, E. Jager, Efficient in vivo priming by vaccination with recombinant NY-ESO-1 protein and CpG in antigen naive prostate cancer patients, Clin Cancer Res, 17 (2011) 861-870. [134] A.B. Bakker, M.W. Schreurs, A.J. de Boer, Y. Kawakami, S.A. Rosenberg, G.J. Adema, C.G. Figdor, Melanocyte lineage-specific antigen gp100 is recognized by melanoma-derived tumor-infiltrating lymphocytes, J Exp Med, 179 (1994) 1005-1009. [135] Y. Kawakami, S. Eliyahu, C.H. Delgado, P.F. Robbins, K. Sakaguchi, E. Appella, J.R. Yannelli, G.J. Adema, T. Miki, S.A. Rosenberg, Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection, Proc Natl Acad Sci U S A, 91 (1994) 6458-6462. [136] M.R. Parkhurst, E.B. Fitzgerald, S. Southwood, A. Sette, S.A. Rosenberg, Y. Kawakami, Identification of a shared HLA-A*0201-restricted T-cell epitope from the melanoma antigen tyrosinase-related protein 2 (TRP2), Cancer Res, 58 (1998) 4895-4901. [137] P. Correale, K. Walmsley, C. Nieroda, S. Zaremba, M. Zhu, J. Schlom, K.Y. Tsang, In vitro generation of human cytotoxic T lymphocytes specific for peptides derived from prostate-specific antigen, J Natl Cancer Inst, 89 (1997) 293-300. [138] K.W. Lam, C.Y. Li, L.T. Yam, T. Sun, G. Lee, S. Ziesmer, Improved immunohistochemical detection of prostatic acid phosphatase by a monoclonal antibody, Prostate, 15 (1989) 13-21. [139] R.H. Vonderheide, W.C. Hahn, J.L. Schultze, L.M. Nadler, The telomerase catalytic subunit is a widely expressed tumor-associated antigen recognized by cytotoxic T lymphocytes, Immunity, 10 (1999) 673-679. [140] M.L. Disis, D.R. Wallace, T.A. Gooley, Y. Dang, M. Slota, H. Lu, A.L. Coveler, J.S. Childs, D.M. Higgins, P.A. Fintak, C. dela Rosa, K. Tietje, J. Link, J. Waisman, L.G. Salazar, Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer, J Clin Oncol, 27 (2009) 4685-4692. [141] K. Chang, I. Pastan, Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers, Proc Natl Acad Sci U S A, 93 (1996) 136-140. [142] O.J. Finn, K.R. Gantt, A.J. Lepisto, S. Pejawar-Gaddy, J. Xue, P.L. Beatty, Importance of MUC1 and spontaneous mouse tumor models for understanding the immunobiology of human adenocarcinomas, Immunol Res, 50 (2011) 261-268. [143] S.R. Pedersen, M.R. Sorensen, S. Buus, J.P. Christensen, A.R. Thomsen, Comparison of vaccine-induced effector CD8 T cell responses directed against self- and non-self-tumor antigens: implications for cancer immunotherapy, J Immunol, 191 (2013) 3955-3967. [144] W.W. Overwijk, Cancer vaccines in the era of checkpoint blockade: the magic is in the adjuvant, Curr Opin Immunol, 47 (2017) 103-109. [145] J.L. Gulley, P.M. Arlen, R.A. Madan, K.Y. Tsang, M.P. Pazdur, L. Skarupa, J.L. Jones, D.J. Poole, J.P. Higgins, J.W. Hodge, V. Cereda, M. Vergati, S.M. Steinberg, S. Halabi, E. Jones, C. Chen, H. Parnes, J.J. Wright, W.L. Dahut, J. Schlom, Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer, Cancer Immunol Immunother, 59 (2010) 663-674. [146] P. Romero, J. Banchereau, N. Bhardwaj, M. Cockett, M.L. Disis, G. Dranoff, E. Gilboa, S.A. Hammond, R. Hershberg, A.J. Korman, P. Kvistborg, C. Melief, I. Mellman, A.K. Palucka, I. Redchenko, H. Robins, F. Sallusto, T. Schenkelberg, S. Schoenberger, J. Sosman, O. Tureci, B. Van den Eynde, W. Koff, G. Coukos, The Human Vaccines Project: A roadmap for cancer vaccine development, Sci Transl Med, 8 (2016) 334ps339. [147] J.D. Miller, R.G. van der Most, R.S. Akondy, J.T. Glidewell, S. Albott, D. Masopust, K. Murali-Krishna, P.L. Mahar, S. Edupuganti, S. Lalor, S. Germon, C. Del Rio, M.J. Mulligan, S.I. Staprans, J.D. Altman, M.B. Feinberg, R. Ahmed, Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines, Immunity, 28 (2008) 710-722. [148] M.R. Parkhurst, J.C. Yang, R.C. Langan, M.E. Dudley, D.A. Nathan, S.A. Feldman, J.L. Davis, R.A. Morgan, M.J. Merino, R.M. Sherry, M.S. Hughes, U.S. Kammula, G.Q. Phan, R.M. Lim, S.A. Wank, N.P. Restifo, P.F. Robbins, C.M. Laurencot, S.A. Rosenberg, T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis, Mol Ther, 19 (2011) 620-626. [149] P.K. Srivastava, Neoepitopes of Cancers: Looking Back, Looking Ahead, Cancer Immunol Res, 3 (2015) 969-977. [150] R.T. Prehn, J.M. Main, Immunity to methylcholanthrene-induced sarcomas, J Natl Cancer Inst, 18 (1957) 769-778. [151] T. Wolfel, M. Hauer, J. Schneider, M. Serrano, C. Wolfel, E. Klehmann-Hieb, E. De Plaen, T. Hankeln, K.H. Meyer zum Buschenfelde, D. Beach, A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma, Science, 269 (1995) 1281-1284. [152] P.G. Coulie, F. Lehmann, B. Lethe, J. Herman, C. Lurquin, M. Andrawiss, T. Boon, A mutated intron sequence codes for an antigenic peptide recognized by cytolytic T lymphocytes on a human melanoma, Proc Natl Acad Sci U S A, 92 (1995) 7976-7980. [153] S. Tanzarella, V. Russo, I. Lionello, P. Dalerba, D. Rigatti, C. Bordignon, C. Traversari, Identification of a promiscuous T-cell epitope encoded by multiple members of the MAGE family, Cancer Res, 59 (1999) 2668-2674. [154] I. Melero, G. Gaudernack, W. Gerritsen, C. Huber, G. Parmiani, S. Scholl, N. Thatcher, J. Wagstaff, C. Zielinski, I. Faulkner, H. Mellstedt, Therapeutic vaccines for cancer: an overview of clinical trials, Nat Rev Clin Oncol, 11 (2014) 509-524. [155] H. Matsushita, M.D. Vesely, D.C. Koboldt, C.G. Rickert, R. Uppaluri, V.J. Magrini, C.D. Arthur, J.M. White, Y.S. Chen, L.K. Shea, J. Hundal, M.C. Wendl, R. Demeter, T. Wylie, J.P. Allison, M.J. Smyth, L.J. Old, E.R. Mardis, R.D. Schreiber, Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting, Nature, 482 (2012) 400-404. [156] J.C. Castle, S. Kreiter, J. Diekmann, M. Lower, N. van de Roemer, J. de Graaf, A. Selmi, M. Diken, S. Boegel, C. Paret, M. Koslowski, A.N. Kuhn, C.M. Britten, C. Huber, O. Tureci, U. Sahin, Exploiting the mutanome for tumor vaccination, Cancer Res, 72 (2012) 1081-1091. [157] V. Roudko, B. Greenbaum, N. Bhardwaj, Computational Prediction and Validation of Tumor-Associated Neoantigens, Front Immunol, 11 (2020) 27. [158] illumina, Planning your NGS budget. [159] T.N. Schumacher, R.D. Schreiber, Neoantigens in cancer immunotherapy, Science, 348 (2015) 69-74. [160] M. Yarchoan, B.A. Johnson, 3rd, E.R. Lutz, D.A. Laheru, E.M. Jaffee, Targeting neoantigens to augment antitumour immunity, Nat Rev Cancer, 17 (2017) 209-222. [161] J.P. Ward, M.M. Gubin, R.D. Schreiber, The Role of Neoantigens in Naturally Occurring and Therapeutically Induced Immune Responses to Cancer, Adv Immunol, 130 (2016) 25-74. [162] M.M. Gubin, X. Zhang, H. Schuster, E. Caron, J.P. Ward, T. Noguchi, Y. Ivanova, J. Hundal, C.D. Arthur, W.J. Krebber, G.E. Mulder, M. Toebes, M.D. Vesely, S.S. Lam, A.J. Korman, J.P. Allison, G.J. Freeman, A.H. Sharpe, E.L. Pearce, T.N. Schumacher, R. Aebersold, H.G. Rammensee, C.J. Melief, E.R. Mardis, W.E. Gillanders, M.N. Artyomov, R.D. Schreiber, Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens, Nature, 515 (2014) 577-581. [163] S. Kreiter, M. Vormehr, N. van de Roemer, M. Diken, M. Lower, J. Diekmann, S. Boegel, B. Schrors, F. Vascotto, J.C. Castle, A.D. Tadmor, S.P. Schoenberger, C. Huber, O. Tureci, U. Sahin, Mutant MHC class II epitopes drive therapeutic immune responses to cancer, Nature, 520 (2015) 692-696. [164] P.F. Robbins, Y.C. Lu, M. El-Gamil, Y.F. Li, C. Gross, J. Gartner, J.C. Lin, J.K. Teer, P. Cliften, E. Tycksen, Y. Samuels, S.A. Rosenberg, Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells, Nat Med, 19 (2013) 747-752. [165] N. van Rooij, M.M. van Buuren, D. Philips, A. Velds, M. Toebes, B. Heemskerk, L.J. van Dijk, S. Behjati, H. Hilkmann, D. El Atmioui, M. Nieuwland, M.R. Stratton, R.M. Kerkhoven, C. Kesmir, J.B. Haanen, P. Kvistborg, T.N. Schumacher, Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma, J Clin Oncol, 31 (2013) e439-442. [166] D.T. Le, J.N. Durham, K.N. Smith, H. Wang, B.R. Bartlett, L.K. Aulakh, S. Lu, H. Kemberling, C. Wilt, B.S. Luber, F. Wong, N.S. Azad, A.A. Rucki, D. Laheru, R. Donehower, A. Zaheer, G.A. Fisher, T.S. Crocenzi, J.J. Lee, T.F. Greten, A.G. Duffy, K.K. Ciombor, A.D. Eyring, B.H. Lam, A. Joe, S.P. Kang, M. Holdhoff, L. Danilova, L. Cope, C. Meyer, S. Zhou, R.M. Goldberg, D.K. Armstrong, K.M. Bever, A.N. Fader, J. Taube, F. Housseau, D. Spetzler, N. Xiao, D.M. Pardoll, N. Papadopoulos, K.W. Kinzler, J.R. Eshleman, B. Vogelstein, R.A. Anders, L.A. Diaz, Jr., Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade, Science, 357 (2017) 409-413. [167] P.A. Ott, Z. Hu, D.B. Keskin, S.A. Shukla, J. Sun, D.J. Bozym, W. Zhang, A. Luoma, A. Giobbie-Hurder, L. Peter, C. Chen, O. Olive, T.A. Carter, S. Li, D.J. Lieb, T. Eisenhaure, E. Gjini, J. Stevens, W.J. Lane, I. Javeri, K. Nellaiappan, A.M. Salazar, H. Daley, M. Seaman, E.I. Buchbinder, C.H. Yoon, M. Harden, N. Lennon, S. Gabriel, S.J. Rodig, D.H. Barouch, J.C. Aster, G. Getz, K. Wucherpfennig, D. Neuberg, J. Ritz, E.S. Lander, E.F. Fritsch, N. Hacohen, C.J. Wu, An immunogenic personal neoantigen vaccine for patients with melanoma, Nature, 547 (2017) 217-221. [168] U. Sahin, E. Derhovanessian, M. Miller, B.P. Kloke, P. Simon, M. Lower, V. Bukur, A.D. Tadmor, U. Luxemburger, B. Schrors, T. Omokoko, M. Vormehr, C. Albrecht, A. Paruzynski, A.N. Kuhn, J. Buck, S. Heesch, K.H. Schreeb, F. Muller, I. Ortseifer, I. Vogler, E. Godehardt, S. Attig, R. Rae, A. Breitkreuz, C. Tolliver, M. Suchan, G. Martic, A. Hohberger, P. Sorn, J. Diekmann, J. Ciesla, O. Waksmann, A.K. Bruck, M. Witt, M. Zillgen, A. Rothermel, B. Kasemann, D. Langer, S. Bolte, M. Diken, S. Kreiter, R. Nemecek, C. Gebhardt, S. Grabbe, C. Holler, J. Utikal, C. Huber, C. Loquai, O. Tureci, Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer, Nature, 547 (2017) 222-226. [169] Z. Hu, D.E. Leet, R.L. Allesoe, G. Oliveira, S. Li, A.M. Luoma, J. Liu, J. Forman, T. Huang, J.B. Iorgulescu, R. Holden, S. Sarkizova, S.H. Gohil, R.A. Redd, J. Sun, L. Elagina, A. Giobbie-Hurder, W. Zhang, L. Peter, Z. Ciantra, S. Rodig, O. Olive, K. Shetty, J. Pyrdol, M. Uduman, P.C. Lee, P. Bachireddy, E.I. Buchbinder, C.H. Yoon, D. Neuberg, B.L. Pentelute, N. Hacohen, K.J. Livak, S.A. Shukla, L.R. Olsen, D.H. Barouch, K.W. Wucherpfennig, E.F. Fritsch, D.B. Keskin, C.J. Wu, P.A. Ott, Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma, Nat Med, 27 (2021) 515-525. [170] D.B. Keskin, A.J. Anandappa, J. Sun, I. Tirosh, N.D. Mathewson, S. Li, G. Oliveira, A. Giobbie-Hurder, K. Felt, E. Gjini, S.A. Shukla, Z. Hu, L. Li, P.M. Le, R.L. Allesoe, A.R. Richman, M.S. Kowalczyk, S. Abdelrahman, J.E. Geduldig, S. Charbonneau, K. Pelton, J.B. Iorgulescu, L. Elagina, W. Zhang, O. Olive, C. McCluskey, L.R. Olsen, J. Stevens, W.J. Lane, A.M. Salazar, H. Daley, P.Y. Wen, E.A. Chiocca, M. Harden, N.J. Lennon, S. Gabriel, G. Getz, E.S. Lander, A. Regev, J. Ritz, D. Neuberg, S.J. Rodig, K.L. Ligon, M.L. Suva, K.W. Wucherpfennig, N. Hacohen, E.F. Fritsch, K.J. Livak, P.A. Ott, C.J. Wu, D.A. Reardon, Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial, Nature, 565 (2019) 234-239. [171] N. Hilf, S. Kuttruff-Coqui, K. Frenzel, V. Bukur, S. Stevanovic, C. Gouttefangeas, M. Platten, G. Tabatabai, V. Dutoit, S.H. van der Burg, P. Thor Straten, F. Martinez-Ricarte, B. Ponsati, H. Okada, U. Lassen, A. Admon, C.H. Ottensmeier, A. Ulges, S. Kreiter, A. von Deimling, M. Skardelly, D. Migliorini, J.R. Kroep, M. Idorn, J. Rodon, J. Piro, H.S. Poulsen, B. Shraibman, K. McCann, R. Mendrzyk, M. Lower, M. Stieglbauer, C.M. Britten, D. Capper, M.J.P. Welters, J. Sahuquillo, K. Kiesel, E. Derhovanessian, E. Rusch, L. Bunse, C. Song, S. Heesch, C. Wagner, A. Kemmer-Bruck, J. Ludwig, J.C. Castle, O. Schoor, A.D. Tadmor, E. Green, J. Fritsche, M. Meyer, N. Pawlowski, S. Dorner, F. Hoffgaard, B. Rossler, D. Maurer, T. Weinschenk, C. Reinhardt, C. Huber, H.G. Rammensee, H. Singh-Jasuja, U. Sahin, P.Y. Dietrich, W. Wick, Actively personalized vaccination trial for newly diagnosed glioblastoma, Nature, 565 (2019) 240-245. [172] P.A. Ott, S. Hu-Lieskovan, B. Chmielowski, R. Govindan, A. Naing, N. Bhardwaj, K. Margolin, M.M. Awad, M.D. Hellmann, J.J. Lin, T. Friedlander, M.E. Bushway, K.N. Balogh, T.E. Sciuto, V. Kohler, S.J. Turnbull, R. Besada, R.R. Curran, B. Trapp, J. Scherer, A. Poran, D. Harjanto, D. Barthelme, Y.S. Ting, J.Z. Dong, Y. Ware, Y. Huang, Z. Huang, A. Wanamaker, L.D. Cleary, M.A. Moles, K. Manson, J. Greshock, Z.S. Khondker, E. Fritsch, M.S. Rooney, M. DeMario, R.B. Gaynor, L. Srinivasan, A Phase Ib Trial of Personalized Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer, Cell, 183 (2020) 347-362 e324. [173] G. Cafri, J.J. Gartner, T. Zaks, K. Hopson, N. Levin, B.C. Paria, M.R. Parkhurst, R. Yossef, F.J. Lowery, M.S. Jafferji, T.D. Prickett, S.L. Goff, C.T. McGowan, S. Seitter, M.L. Shindorf, A. Parikh, P.D. Chatani, P.F. Robbins, S.A. Rosenberg, mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer, J Clin Invest, 130 (2020) 5976-5988. [174] S. Bhatia, N.J. Miller, H. Lu, N.V. Longino, D. Ibrani, M.M. Shinohara, D.R. Byrd, U. Parvathaneni, R. Kulikauskas, J. Ter Meulen, F.J. Hsu, D.M. Koelle, P. Nghiem, Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma, Clin Cancer Res, 25 (2019) 1185-1195. [175] M.J. Frank, P.M. Reagan, N.L. Bartlett, L.I. Gordon, J.W. Friedberg, D.K. Czerwinski, S.R. Long, R.T. Hoppe, R. Janssen, A.F. Candia, R.L. Coffman, R. Levy, In Situ Vaccination with a TLR9 Agonist and Local Low-Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma, Cancer Discov, 8 (2018) 1258-1269. [176] L. Corrales, L.H. Glickman, S.M. McWhirter, D.B. Kanne, K.E. Sivick, G.E. Katibah, S.R. Woo, E. Lemmens, T. Banda, J.J. Leong, K. Metchette, T.W. Dubensky, Jr., T.F. Gajewski, Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity, Cell Rep, 11 (2015) 1018-1030. [177] J.M. Ramanjulu, G.S. Pesiridis, J. Yang, N. Concha, R. Singhaus, S.Y. Zhang, J.L. Tran, P. Moore, S. Lehmann, H.C. Eberl, M. Muelbaier, J.L. Schneck, J. Clemens, M. Adam, J. Mehlmann, J. Romano, A. Morales, J. Kang, L. Leister, T.L. Graybill, A.K. Charnley, G. Ye, N. Nevins, K. Behnia, A.I. Wolf, V. Kasparcova, K. Nurse, L. Wang, A.C. Puhl, Y. Li, M. Klein, C.B. Hopson, J. Guss, M. Bantscheff, G. Bergamini, M.A. Reilly, Y. Lian, K.J. Duffy, J. Adams, K.P. Foley, P.J. Gough, R.W. Marquis, J. Smothers, A. Hoos, J. Bertin, Design of amidobenzimidazole STING receptor agonists with systemic activity, Nature, 564 (2018) 439-443. [178] I. Lurje, W. Werner, R. Mohr, C. Roderburg, F. Tacke, L. Hammerich, In Situ Vaccination as a Strategy to Modulate the Immune Microenvironment of Hepatocellular Carcinoma, Front Immunol, 12 (2021) 650486. [179] L. Hammerich, A. Binder, J.D. Brody, In situ vaccination: Cancer immunotherapy both personalized and off-the-shelf, Mol Oncol, 9 (2015) 1966-1981. [180] G. Redelman-Sidi, M.S. Glickman, B.H. Bochner, The mechanism of action of BCG therapy for bladder cancer--a current perspective, Nat Rev Urol, 11 (2014) 153-162. [181] P. Kamath, E. Darwin, H. Arora, K. Nouri, A Review on Imiquimod Therapy and Discussion on Optimal Management of Basal Cell Carcinomas, Clin Drug Investig, 38 (2018) 883-899. [182] S.M. Reddy, M. Carter, I. Chan, M. Hullings, N. Unni, J. Medina, S. Shakeel, S. Armstrong, L. Cade, F.J. Fattah, C. Ahn, Y.V. Fang, N. Chen, H.L. McArthur, N. Sinclair, M.J. Yellin, J. O'Shaughnessy, R. Nanda, S.D. Conzen, C.L. Arteaga, Phase 1 pilot study with dose expansion of chemotherapy in combination with CD40 agonist and Flt3 ligand in metastatic triple-negative breast cancer, Journal of Clinical Oncology, 40 (2022) TPS1126-TPS1126. [183] H. Salmon, J. Idoyaga, A. Rahman, M. Leboeuf, R. Remark, S. Jordan, M. Casanova-Acebes, M. Khudoynazarova, J. Agudo, N. Tung, S. Chakarov, C. Rivera, B. Hogstad, M. Bosenberg, D. Hashimoto, S. Gnjatic, N. Bhardwaj, A.K. Palucka, B.D. Brown, J. Brody, F. Ginhoux, M. Merad, Expansion and Activation of CD103(+) Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition, Immunity, 44 (2016) 924-938. [184] J. Heo, T. Reid, L. Ruo, C.J. Breitbach, S. Rose, M. Bloomston, M. Cho, H.Y. Lim, H.C. Chung, C.W. Kim, J. Burke, R. Lencioni, T. Hickman, A. Moon, Y.S. Lee, M.K. Kim, M. Daneshmand, K. Dubois, L. Longpre, M. Ngo, C. Rooney, J.C. Bell, B.G. Rhee, R. Patt, T.H. Hwang, D.H. Kirn, Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer, Nat Med, 19 (2013) 329-336. [185] L. Siu, J. Brody, S. Gupta, A. Marabelle, A. Jimeno, P. Munster, J. Grilley-Olson, A.H. Rook, A. Hollebecque, R.K.S. Wong, J.W. Welsh, Y. Wu, C. Morehouse, O. Hamid, F. Walcott, Z.A. Cooper, R. Kumar, C. Ferte, D.S. Hong, Safety and clinical activity of intratumoral MEDI9197 alone and in combination with durvalumab and/or palliative radiation therapy in patients with advanced solid tumors, J Immunother Cancer, 8 (2020). [186] T. Bekaii-Saab, R. Wesolowski, D.H. Ahn, C. Wu, A. Mortazavi, M. Lustberg, B. Ramaswamy, J. Fowler, L. Wei, J. Overholser, P.T.P. Kaumaya, Phase I Immunotherapy Trial with Two Chimeric HER-2 B-Cell Peptide Vaccines Emulsified in Montanide ISA 720VG and Nor-MDP Adjuvant in Patients with Advanced Solid Tumors, Clin Cancer Res, 25 (2019) 3495-3507. [187] J. Ji, W.R. Park, S. Cho, Y. Yang, W. Li, K. Harris, X. Huang, S. Gu, D.H. Kim, Z. Zhang, A.C. Larson, Iron-Oxide Nanocluster Labeling of Clostridium novyi-NT Spores for MR Imaging-Monitored Locoregional Delivery to Liver Tumors in Rat and Rabbit Models, J Vasc Interv Radiol, 30 (2019) 1106-1115 e1101. [188] L. Hammerich, T.U. Marron, R. Upadhyay, J. Svensson-Arvelund, M. Dhainaut, S. Hussein, Y. Zhan, D. Ostrowski, M. Yellin, H. Marsh, A.M. Salazar, A.H. Rahman, B.D. Brown, M. Merad, J.D. Brody, Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination, Nat Med, 25 (2019) 814-824. [189] H. Wang, A.J. Najibi, M.C. Sobral, B.R. Seo, J.Y. Lee, D. Wu, A.W. Li, C.S. Verbeke, D.J. Mooney, Biomaterial-based scaffold for in situ chemo-immunotherapy to treat poorly immunogenic tumors, Nat Commun, 11 (2020) 5696. [190] E.M. Cheng, N.W. Tsarovsky, P.M. Sondel, A.L. Rakhmilevich, Interleukin-12 as an in situ cancer vaccine component: a review, Cancer Immunol Immunother, (2022). [191] M. Caskey, F. Lefebvre, A. Filali-Mouhim, M.J. Cameron, J.P. Goulet, E.K. Haddad, G. Breton, C. Trumpfheller, S. Pollak, I. Shimeliovich, A. Duque-Alarcon, L. Pan, A. Nelkenbaum, A.M. Salazar, S.J. Schlesinger, R.M. Steinman, R.P. Sekaly, Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans, J Exp Med, 208 (2011) 2357-2366. [192] X. Zhao, M. Ai, Y. Guo, X. Zhou, L. Wang, X. Li, C. Yao, Poly I:C-induced tumor cell apoptosis mediated by pattern-recognition receptors, Cancer Biother Radiopharm, 27 (2012) 530-534. [193] M.A. Aznar, L. Planelles, M. Perez-Olivares, C. Molina, S. Garasa, I. Etxeberria, G. Perez, I. Rodriguez, E. Bolanos, P. Lopez-Casas, M.E. Rodriguez-Ruiz, J.L. Perez-Gracia, I. Marquez-Rodas, A. Teijeira, M. Quintero, I. Melero, Immunotherapeutic effects of intratumoral nanoplexed poly I:C, J Immunother Cancer, 7 (2019) 116. [194] A.M. Salazar, E. Celis, Double-Stranded RNA Immunomodulators in Prostate Cancer, Urol Clin North Am, 47 (2020) e1-e8. [195] A.N. de la Torre, S. Contractor, I. Castaneda, C.S. Cathcart, D. Razdan, D. Klyde, P. Kisza, S.F. Gonzales, A.M. Salazar, A Phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect, J Hepatocell Carcinoma, 4 (2017) 111-121. [196] H. Sultan, A.M. Salazar, E. Celis, Poly-ICLC, a multi-functional immune modulator for treating cancer, Semin Immunol, (2020) 101414. [197] H. Sultan, J. Wu, V.I. Fesenkova, A.E. Fan, D. Addis, A.M. Salazar, E. Celis, Poly-IC enhances the effectiveness of cancer immunotherapy by promoting T cell tumor infiltration, J Immunother Cancer, 8 (2020). [198] A.M. Salazar, R.B. Erlich, A. Mark, N. Bhardwaj, R.B. Herberman, Therapeutic in situ autovaccination against solid cancers with intratumoral poly-ICLC: case report, hypothesis, and clinical trial, Cancer Immunol Res, 2 (2014) 720-724. [199] C. Kyi, V. Roudko, R. Sabado, Y. Saenger, W. Loging, J. Mandeli, T.H. Thin, D. Lehrer, M. Donovan, M. Posner, K. Misiukiewicz, B. Greenbaum, A. Salazar, P. Friedlander, N. Bhardwaj, Therapeutic Immune Modulation against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial, Clin Cancer Res, 24 (2018) 4937-4948. [200] D. Hanahan, Hallmarks of Cancer: New Dimensions, Cancer Discov, 12 (2022) 31-46. [201] P. Danaher, S. Warren, L. Dennis, L. D'Amico, A. White, M.L. Disis, M.A. Geller, K. Odunsi, J. Beechem, S.P. Fling, Gene expression markers of Tumor Infiltrating Leukocytes, J Immunother Cancer, 5 (2017) 18. [202] M.V. Guerin, V. Finisguerra, B.J. Van den Eynde, N. Bercovici, A. Trautmann, Preclinical murine tumor models: a structural and functional perspective, Elife, 9 (2020). [203] J.E. Talmadge, R.K. Singh, I.J. Fidler, A. Raz, Murine models to evaluate novel and conventional therapeutic strategies for cancer, Am J Pathol, 170 (2007) 793-804. [204] M.C. Bibby, Orthotopic models of cancer for preclinical drug evaluation: advantages and disadvantages, Eur J Cancer, 40 (2004) 852-857. [205] A. Choudhury, N. Moniaux, A.B. Ulrich, B.M. Schmied, J. Standop, P.M. Pour, S.J. Gendler, M.A. Hollingsworth, J.P. Aubert, S.K. Batra, MUC4 mucin expression in human pancreatic tumours is affected by organ environment: the possible role of TGFbeta2, Br J Cancer, 90 (2004) 657-664. [206] M.V. Guerin, F. Regnier, V. Feuillet, L. Vimeux, J.M. Weiss, G. Bismuth, G. Altan-Bonnet, T. Guilbert, M. Thoreau, V. Finisguerra, E. Donnadieu, A. Trautmann, N. Bercovici, TGFbeta blocks IFNalpha/beta release and tumor rejection in spontaneous mammary tumors, Nat Commun, 10 (2019) 4131. [207] J.H. Newman, C.B. Chesson, N.L. Herzog, P.K. Bommareddy, S.M. Aspromonte, R. Pepe, R. Estupinian, M.M. Aboelatta, S. Buddhadev, S. Tarabichi, M. Lee, S. Li, D.J. Medina, E.F. Giurini, K.H. Gupta, G. Guevara-Aleman, M. Rossi, C. Nowicki, A. Abed, J.W. Goldufsky, J.R. Broucek, R.E. Redondo, D. Rotter, S.R. Jhawar, S.J. Wang, F.J. Kohlhapp, H.L. Kaufman, P.G. Thomas, V. Gupta, T.M. Kuzel, J. Reiser, J. Paras, M.P. Kane, E.A. Singer, J. Malhotra, L.K. Denzin, D.B. Sant'Angelo, A.B. Rabson, L.Y. Lee, A. Lasfar, J. Langenfeld, J.M. Schenkel, M.J. Fidler, E.S. Ruiz, A.L. Marzo, J.S. Rudra, A.W. Silk, A. Zloza, Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer, Proc Natl Acad Sci U S A, 117 (2020) 1119-1128. [208] W.A. Muller, Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response, Trends Immunol, 24 (2003) 327-334. [209] P. Johnson, A. Maiti, K.L. Brown, R. Li, A role for the cell adhesion molecule CD44 and sulfation in leukocyte-endothelial cell adhesion during an inflammatory response?, Biochem Pharmacol, 59 (2000) 455-465. [210] D.L. Ou, Y.Y. Lin, C.L. Hsu, Y.Y. Lin, C.W. Chen, J.S. Yu, S.C. Miaw, P.N. Hsu, A.L. Cheng, C. Hsu, Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma, Liver Cancer, 8 (2019) 155-171. [211] Y. Jin, X. An, B. Mao, R. Sun, R. Kumari, X. Chen, Y. Shan, M. Zang, L. Xu, J. Muntel, K. Beeler, R. Bruderer, L. Reiter, S. Guo, D. Zhou, Q.X. Li, X. Ouyang, Different syngeneic tumors show distinctive intrinsic tumor-immunity and mechanisms of actions (MOA) of anti-PD-1 treatment, Sci Rep, 12 (2022) 3278. [212] G. Bour, F. Martel, L. Goffin, B. Bayle, J. Gangloff, M. Aprahamian, J. Marescaux, J.M. Egly, Design and development of a robotized system coupled to microCT imaging for intratumoral drug evaluation in a HCC mouse model, PLoS One, 9 (2014) e106675. [213] D. Friedman, J.R. Baird, K.H. Young, B. Cottam, M.R. Crittenden, S. Friedman, M.J. Gough, P. Newell, Programmed cell death-1 blockade enhances response to stereotactic radiation in an orthotopic murine model of hepatocellular carcinoma, Hepatol Res, 47 (2017) 702-714. [214] C. Hage, S. Hoves, M. Ashoff, V. Schandl, S. Hort, N. Rieder, C. Heichinger, M. Berrera, C.H. Ries, F. Kiessling, T. Poschinger, Characterizing responsive and refractory orthotopic mouse models of hepatocellular carcinoma in cancer immunotherapy, PLoS One, 14 (2019) e0219517. [215] C.F. Teng, T. Wang, T.H. Wu, J.H. Lin, F.Y. Shih, W.C. Shyu, L.B. Jeng, Combination therapy with dendritic cell vaccine and programmed death ligand 1 immune checkpoint inhibitor for hepatocellular carcinoma in an orthotopic mouse model, Ther Adv Med Oncol, 12 (2020) 1758835920922034. [216] B. Lacoste, V.A. Raymond, S. Cassim, P. Lapierre, M. Bilodeau, Highly tumorigenic hepatocellular carcinoma cell line with cancer stem cell-like properties, PLoS One, 12 (2017) e0171215. [217] F. Lang, B. Schrors, M. Lower, O. Tureci, U. Sahin, Identification of neoantigens for individualized therapeutic cancer vaccines, Nat Rev Drug Discov, 21 (2022) 261-282. [218] E. Alspach, D.M. Lussier, A.P. Miceli, I. Kizhvatov, M. DuPage, A.M. Luoma, W. Meng, C.F. Lichti, E. Esaulova, A.N. Vomund, D. Runci, J.P. Ward, M.M. Gubin, R.F.V. Medrano, C.D. Arthur, J.M. White, K.C.F. Sheehan, A. Chen, K.W. Wucherpfennig, T. Jacks, E.R. Unanue, M.N. Artyomov, R.D. Schreiber, MHC-II neoantigens shape tumour immunity and response to immunotherapy, Nature, 574 (2019) 696-701. [219] X. Chen, J. Yang, L. Wang, B. Liu, Personalized neoantigen vaccination with synthetic long peptides: recent advances and future perspectives, Theranostics, 10 (2020) 6011-6023. [220] K.L. Rock, E. Reits, J. Neefjes, Present Yourself! By MHC Class I and MHC Class II Molecules, Trends Immunol, 37 (2016) 724-737. [221] W. Ma, V. Stroobant, C. Heirman, Z. Sun, K. Thielemans, A. Mulder, P. van der Bruggen, B.J. Van den Eynde, The Vacuolar Pathway of Long Peptide Cross-Presentation Can Be TAP Dependent, J Immunol, 202 (2019) 451-459. [222] J. Menager, F. Ebstein, R. Oger, P. Hulin, S. Nedellec, E. Duverger, A. Lehmann, P.M. Kloetzel, F. Jotereau, Y. Guilloux, Cross-presentation of synthetic long peptides by human dendritic cells: a process dependent on ERAD component p97/VCP but Not sec61 and/or Derlin-1, PLoS One, 9 (2014) e89897. [223] T. Sathaliyawala, M. Kubota, N. Yudanin, D. Turner, P. Camp, J.J. Thome, K.L. Bickham, H. Lerner, M. Goldstein, M. Sykes, T. Kato, D.L. Farber, Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets, Immunity, 38 (2013) 187-197. [224] J.M. Schenkel, K.A. Fraser, V. Vezys, D. Masopust, Sensing and alarm function of resident memory CD8(+) T cells, Nat Immunol, 14 (2013) 509-513. [225] H. Shin, A. Iwasaki, A vaccine strategy that protects against genital herpes by establishing local memory T cells, Nature, 491 (2012) 463-467. [226] T. Wu, Y. Hu, Y.T. Lee, K.R. Bouchard, A. Benechet, K. Khanna, L.S. Cauley, Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection, J Leukoc Biol, 95 (2014) 215-224. [227] J.M. Schenkel, K.A. Fraser, L.K. Beura, K.E. Pauken, V. Vezys, D. Masopust, T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses, Science, 346 (2014) 98-101. [228] S. Ariotti, M.A. Hogenbirk, F.E. Dijkgraaf, L.L. Visser, M.E. Hoekstra, J.Y. Song, H. Jacobs, J.B. Haanen, T.N. Schumacher, T cell memory. Skin-resident memory CD8(+) T cells trigger a state of tissue-wide pathogen alert, Science, 346 (2014) 101-105. [229] S.R. Bennett, F.R. Carbone, F. Karamalis, J.F. Miller, W.R. Heath, Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help, J Exp Med, 186 (1997) 65-70. [230] J.P. Ridge, F. Di Rosa, P. Matzinger, A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell, Nature, 393 (1998) 474-478. [231] U. Boehm, T. Klamp, M. Groot, J.C. Howard, Cellular responses to interferon-gamma, Annu Rev Immunol, 15 (1997) 749-795. [232] M.M. Tomayko, C.P. Reynolds, Determination of subcutaneous tumor size in athymic (nude) mice, Cancer Chemother Pharmacol, 24 (1989) 148-154. [233] T.F. Vandamme, Use of rodents as models of human diseases, J Pharm Bioallied Sci, 6 (2014) 2-9. [234] M.W. Heijstek, O. Kranenburg, I.H. Borel Rinkes, Mouse models of colorectal cancer and liver metastases, Dig Surg, 22 (2005) 16-25. [235] X. Zhao, L. Li, T.K. Starr, S. Subramanian, Tumor location impacts immune response in mouse models of colon cancer, Oncotarget, 8 (2017) 54775-54787. [236] T.L. Whiteside, The tumor microenvironment and its role in promoting tumor growth, Oncogene, 27 (2008) 5904-5912. [237] G.L. Beatty, W.L. Gladney, Immune escape mechanisms as a guide for cancer immunotherapy, Clin Cancer Res, 21 (2015) 687-692. [238] R.D. Schreiber, L.J. Old, M.J. Smyth, Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion, Science, 331 (2011) 1565-1570. [239] H.I. Cho, K. Barrios, Y.R. Lee, A.K. Linowski, E. Celis, BiVax: a peptide/poly-IC subunit vaccine that mimics an acute infection elicits vast and effective anti-tumor CD8 T-cell responses, Cancer Immunol Immunother, 62 (2013) 787-799. [240] T. Nagato, Y.R. Lee, Y. Harabuchi, E. Celis, Combinatorial immunotherapy of polyinosinic-polycytidylic acid and blockade of programmed death-ligand 1 induce effective CD8 T-cell responses against established tumors, Clin Cancer Res, 20 (2014) 1223-1234. [241] A.M. D'Alise, G. Leoni, G. Cotugno, F. Troise, F. Langone, I. Fichera, M. De Lucia, L. Avalle, R. Vitale, A. Leuzzi, V. Bignone, E. Di Matteo, F.G. Tucci, V. Poli, A. Lahm, M.T. Catanese, A. Folgori, S. Colloca, A. Nicosia, E. Scarselli, Adenoviral vaccine targeting multiple neoantigens as strategy to eradicate large tumors combined with checkpoint blockade, Nat Commun, 10 (2019) 2688. [242] R. Kuai, L.J. Ochyl, K.S. Bahjat, A. Schwendeman, J.J. Moon, Designer vaccine nanodiscs for personalized cancer immunotherapy, Nat Mater, 16 (2017) 489-496. [243] H.L. Kinkead, A. Hopkins, E. Lutz, A.A. Wu, M. Yarchoan, K. Cruz, S. Woolman, T. Vithayathil, L.H. Glickman, C.O. Ndubaku, S.M. McWhirter, T.W. Dubensky, Jr., T.D. Armstrong, E.M. Jaffee, N. Zaidi, Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer, JCI Insight, 3 (2018) e122857. [244] L. Liu, J. Chen, H. Zhang, J. Ye, C. Moore, C. Lu, Y. Fang, Y.X. Fu, B. Li, Concurrent delivery of immune checkpoint blockade modulates T cell dynamics to enhance neoantigen vaccine-generated antitumor immunity, Nat Cancer, 3 (2022) 437-452. [245] M.W. Teng, S.F. Ngiow, A. Ribas, M.J. Smyth, Classifying cancers based on T-cell infiltration and PD-L1, Cancer Res, 75 (2015) 2139-2145. [246] Z. Zhang, H. Zhou, Y. Liu, J. Ren, J. Wang, Q. Sang, Y. Lan, Y. Wu, H. Yuan, W. Ni, G. Tai, Anti-PD1 antibody enhances the anti-tumor efficacy of MUC1-MBP fusion protein vaccine via increasing Th1, Tc1 activity and decreasing the proportion of MDSC in the B16-MUC1 melanoma mouse model, Int Immunopharmacol, 101 (2021) 108173. [247] H. Raskov, A. Orhan, J.P. Christensen, I. Gogenur, Cytotoxic CD8(+) T cells in cancer and cancer immunotherapy, Br J Cancer, 124 (2021) 359-367. [248] B. Farhood, M. Najafi, K. Mortezaee, CD8(+) cytotoxic T lymphocytes in cancer immunotherapy: A review, J Cell Physiol, 234 (2019) 8509-8521. [249] A.S. Baras, C. Drake, J.J. Liu, N. Gandhi, M. Kates, M.O. Hoque, A. Meeker, N. Hahn, J.M. Taube, M.P. Schoenberg, G. Netto, T.J. Bivalacqua, The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder, Oncoimmunology, 5 (2016) e1134412. [250] M. Ayers, J. Lunceford, M. Nebozhyn, E. Murphy, A. Loboda, D.R. Kaufman, A. Albright, J.D. Cheng, S.P. Kang, V. Shankaran, S.A. Piha-Paul, J. Yearley, T.Y. Seiwert, A. Ribas, T.K. McClanahan, IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade, J Clin Invest, 127 (2017) 2930-2940. [251] E.J. Wherry, T cell exhaustion, Nat Immunol, 12 (2011) 492-499. [252] J.F. Grosso, M.V. Goldberg, D. Getnet, T.C. Bruno, H.R. Yen, K.J. Pyle, E. Hipkiss, D.A. Vignali, D.M. Pardoll, C.G. Drake, Functionally distinct LAG-3 and PD-1 subsets on activated and chronically stimulated CD8 T cells, J Immunol, 182 (2009) 6659-6669. [253] J. Matsuzaki, S. Gnjatic, P. Mhawech-Fauceglia, A. Beck, A. Miller, T. Tsuji, C. Eppolito, F. Qian, S. Lele, P. Shrikant, L.J. Old, K. Odunsi, Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer, Proc Natl Acad Sci U S A, 107 (2010) 7875-7880. [254] P.C. Rodriguez, D.G. Quiceno, A.C. Ochoa, L-arginine availability regulates T-lymphocyte cell-cycle progression, Blood, 109 (2007) 1568-1573. [255] S. Nagaraj, K. Gupta, V. Pisarev, L. Kinarsky, S. Sherman, L. Kang, D.L. Herber, J. Schneck, D.I. Gabrilovich, Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer, Nat Med, 13 (2007) 828-835. [256] J. Yu, Y. Wang, F. Yan, P. Zhang, H. Li, H. Zhao, C. Yan, F. Yan, X. Ren, Noncanonical NF-kappaB activation mediates STAT3-stimulated IDO upregulation in myeloid-derived suppressor cells in breast cancer, J Immunol, 193 (2014) 2574-2586. [257] F. Arihara, E. Mizukoshi, M. Kitahara, Y. Takata, K. Arai, T. Yamashita, Y. Nakamoto, S. Kaneko, Increase in CD14+HLA-DR -/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis, Cancer Immunol Immunother, 62 (2013) 1421-1430. [258] R.J. Tesi, MDSC; the most important cell you have never heard of, Trends Pharmacol Sci, 40 (2019) 4-7. [259] L. Strauss, M.A.A. Mahmoud, J.D. Weaver, N.M. Tijaro-Ovalle, A. Christofides, Q. Wang, R. Pal, M. Yuan, J. Asara, N. Patsoukis, V.A. Boussiotis, Targeted deletion of PD-1 in myeloid cells induces antitumor immunity, Sci Immunol, 5 (2020) eaay1863. [260] O.A. Ali, S.A. Lewin, G. Dranoff, D.J. Mooney, Vaccines Combined with Immune Checkpoint Antibodies Promote Cytotoxic T-cell Activity and Tumor Eradication, Cancer Immunol Res, 4 (2016) 95-100. [261] E. Salvatori, L. Lione, M. Compagnone, E. Pinto, A. Conforti, G. Ciliberto, L. Aurisicchio, F. Palombo, Neoantigen cancer vaccine augments anti-CTLA-4 efficacy, NPJ Vaccines, 7 (2022) 15. [262] L. Aurisicchio, E. Salvatori, L. Lione, S. Bandini, M. Pallocca, R. Maggio, M. Fanciulli, F. De Nicola, F. Goeman, G. Ciliberto, A. Conforti, L. Luberto, F. Palombo, Poly-specific neoantigen-targeted cancer vaccines delay patient derived tumor growth, J Exp Clin Cancer Res, 38 (2019) 78. [263] P.S. Bhojnagarwala, A. Perales-Puchalt, N. Cooch, N.Y. Sardesai, D.B. Weiner, A synDNA vaccine delivering neoAg collections controls heterogenous, multifocal murine lung and ovarian tumors via robust T cell generation, Mol Ther Oncolytics, 21 (2021) 278-287. [264] M.J. Chamberlin, D.L. Patterson, Physical and Chemical Characterization of the Ordered Complexes Formed between Polyinosinic Acid, Polycytidylic Acid and Their Deoxyribo-Analogues, J Mol Biol, 12 (1965) 410-428. [265] J. De Waele, T. Verhezen, S. van der Heijden, Z.N. Berneman, M. Peeters, F. Lardon, A. Wouters, E. Smits, A systematic review on poly(I:C) and poly-ICLC in glioblastoma: adjuvants coordinating the unlocking of immunotherapy, J Exp Clin Cancer Res, 40 (2021) 213. [266] V. Ho, T.S. Lim, J. Lee, J. Steinberg, R. Szmyd, M. Tham, J. Yaligar, P. Kaldis, J.P. Abastado, V. Chew, TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression, Oncotarget, 6 (2015) 27252-27266. [267] Y. Estornes, F. Toscano, F. Virard, G. Jacquemin, A. Pierrot, B. Vanbervliet, M. Bonnin, N. Lalaoui, P. Mercier-Gouy, Y. Pacheco, B. Salaun, T. Renno, O. Micheau, S. Lebecque, dsRNA induces apoptosis through an atypical death complex associating TLR3 to caspase-8, Cell Death Differ, 19 (2012) 1482-1494. [268] A. Paone, D. Starace, R. Galli, F. Padula, P. De Cesaris, A. Filippini, E. Ziparo, A. Riccioli, Toll-like receptor 3 triggers apoptosis of human prostate cancer cells through a PKC-alpha-dependent mechanism, Carcinogenesis, 29 (2008) 1334-1342. [269] A. Weber, Z. Kirejczyk, R. Besch, S. Potthoff, M. Leverkus, G. Hacker, Proapoptotic signalling through Toll-like receptor-3 involves TRIF-dependent activation of caspase-8 and is under the control of inhibitor of apoptosis proteins in melanoma cells, Cell Death Differ, 17 (2010) 942-951. [270] S.W. Kashem, M. Haniffa, D.H. Kaplan, Antigen-Presenting Cells in the Skin, Annu Rev Immunol, 35 (2017) 469-499. [271] A.J. Oliver, P.K.H. Lau, A.S. Unsworth, S. Loi, P.K. Darcy, M.H. Kershaw, C.Y. Slaney, Tissue-Dependent Tumor Microenvironments and Their Impact on Immunotherapy Responses, Front Immunol, 9 (2018) 70. [272] L. Hammerich, N. Bhardwaj, H.E. Kohrt, J.D. Brody, In situ vaccination for the treatment of cancer, Immunotherapy, 8 (2016) 315-330. [273] L. Galluzzi, I. Vitale, S.A. Aaronson, J.M. Abrams, D. Adam, P. Agostinis, E.S. Alnemri, L. Altucci, I. Amelio, D.W. Andrews, M. Annicchiarico-Petruzzelli, A.V. Antonov, E. Arama, E.H. Baehrecke, N.A. Barlev, N.G. Bazan, F. Bernassola, M.J.M. Bertrand, K. Bianchi, M.V. Blagosklonny, K. Blomgren, C. Borner, P. Boya, C. Brenner, M. Campanella, E. Candi, D. Carmona-Gutierrez, F. Cecconi, F.K. Chan, N.S. Chandel, E.H. Cheng, J.E. Chipuk, J.A. Cidlowski, A. Ciechanover, G.M. Cohen, M. Conrad, J.R. Cubillos-Ruiz, P.E. Czabotar, V. D'Angiolella, T.M. Dawson, V.L. Dawson, V. De Laurenzi, R. De Maria, K.M. Debatin, R.J. DeBerardinis, M. Deshmukh, N. Di Daniele, F. Di Virgilio, V.M. Dixit, S.J. Dixon, C.S. Duckett, B.D. Dynlacht, W.S. El-Deiry, J.W. Elrod, G.M. Fimia, S. Fulda, A.J. Garcia-Saez, A.D. Garg, C. Garrido, E. Gavathiotis, P. Golstein, E. Gottlieb, D.R. Green, L.A. Greene, H. Gronemeyer, A. Gross, G. Hajnoczky, J.M. Hardwick, I.S. Harris, M.O. Hengartner, C. Hetz, H. Ichijo, M. Jaattela, B. Joseph, P.J. Jost, P.P. Juin, W.J. Kaiser, M. Karin, T. Kaufmann, O. Kepp, A. Kimchi, R.N. Kitsis, D.J. Klionsky, R.A. Knight, S. Kumar, S.W. Lee, J.J. Lemasters, B. Levine, A. Linkermann, S.A. Lipton, R.A. Lockshin, C. Lopez-Otin, S.W. Lowe, T. Luedde, E. Lugli, M. MacFarlane, F. Madeo, M. Malewicz, W. Malorni, G. Manic, J.C. Marine, S.J. Martin, J.C. Martinou, J.P. Medema, P. Mehlen, P. Meier, S. Melino, E.A. Miao, J.D. Molkentin, U.M. Moll, C. Munoz-Pinedo, S. Nagata, G. Nunez, A. Oberst, M. Oren, M. Overholtzer, M. Pagano, T. Panaretakis, M. Pasparakis, J.M. Penninger, D.M. Pereira, S. Pervaiz, M.E. Peter, M. Piacentini, P. Pinton, J.H.M. Prehn, H. Puthalakath, G.A. Rabinovich, M. Rehm, R. Rizzuto, C.M.P. Rodrigues, D.C. Rubinsztein, T. Rudel, K.M. Ryan, E. Sayan, L. Scorrano, F. Shao, Y. Shi, J. Silke, H.U. Simon, A. Sistigu, B.R. Stockwell, A. Strasser, G. Szabadkai, S.W.G. Tait, D. Tang, N. Tavernarakis, A. Thorburn, Y. Tsujimoto, B. Turk, T. Vanden Berghe, P. Vandenabeele, M.G. Vander Heiden, A. Villunger, H.W. Virgin, K.H. Vousden, D. Vucic, E.F. Wagner, H. Walczak, D. Wallach, Y. Wang, J.A. Wells, W. Wood, J. Yuan, Z. Zakeri, B. Zhivotovsky, L. Zitvogel, G. Melino, G. Kroemer, Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018, Cell Death Differ, 25 (2018) 486-541. [274] W.H. Fridman, L. Zitvogel, C. Sautes-Fridman, G. Kroemer, The immune contexture in cancer prognosis and treatment, Nat Rev Clin Oncol, 14 (2017) 717-734. [275] E.B. Golden, L. Apetoh, Radiotherapy and immunogenic cell death, Semin Radiat Oncol, 25 (2015) 11-17. [276] M.Z. Jin, X.P. Wang, Immunogenic Cell Death-Based Cancer Vaccines, Front Immunol, 12 (2021) 697964. [277] O. Schulz, S.S. Diebold, M. Chen, T.I. Naslund, M.A. Nolte, L. Alexopoulou, Y.T. Azuma, R.A. Flavell, P. Liljestrom, C. Reis e Sousa, Toll-like receptor 3 promotes cross-priming to virus-infected cells, Nature, 433 (2005) 887-892. [278] V. Durai, K.M. Murphy, Functions of Murine Dendritic Cells, Immunity, 45 (2016) 719-736. [279] P. Michea, F. Noel, E. Zakine, U. Czerwinska, P. Sirven, O. Abouzid, C. Goudot, A. Scholer-Dahirel, A. Vincent-Salomon, F. Reyal, S. Amigorena, M. Guillot-Delost, E. Segura, V. Soumelis, Adjustment of dendritic cells to the breast-cancer microenvironment is subset specific, Nat Immunol, 19 (2018) 885-897. [280] J.P. Bottcher, C. Reis e Sousa, The Role of Type 1 Conventional Dendritic Cells in Cancer Immunity, Trends Cancer, 4 (2018) 784-792. [281] L.S.Y. Tan, B. Wong, N.R. Gangodu, A.Z.E. Lee, A. Kian Fong Liou, K.S. Loh, H. Li, M. Yann Lim, A.M. Salazar, C.M. Lim, Enhancing the immune stimulatory effects of cetuximab therapy through TLR3 signalling in Epstein-Barr virus (EBV) positive nasopharyngeal carcinoma, Oncoimmunology, 7 (2018) e1500109. [282] M.P. Longhi, C. Trumpfheller, J. Idoyaga, M. Caskey, I. Matos, C. Kluger, A.M. Salazar, M. Colonna, R.M. Steinman, Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant, J Exp Med, 206 (2009) 1589-1602. [283] Y. Feng, Y. Chen, Y. Meng, Q. Cao, Q. Liu, C. Ling, C. Wang, Bufalin Suppresses Migration and Invasion of Hepatocellular Carcinoma Cells Elicited by Poly (I:C) Therapy, Oncoimmunology, 7 (2018) e1426434. [284] Y.Y. Xu, L. Chen, G.L. Wang, J.M. Zhou, Y.X. Zhang, Y.Z. Wei, Y.Y. Zhu, J. Qin, A synthetic dsRNA, as a TLR3 pathwaysynergist, combined with sorafenib suppresses HCC in vitro and in vivo, BMC Cancer, 13 (2013) 527. [285] S. Chikuma, S. Terawaki, T. Hayashi, R. Nabeshima, T. Yoshida, S. Shibayama, T. Okazaki, T. Honjo, PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo, J Immunol, 182 (2009) 6682-6689. [286] C. Badoual, S. Hans, N. Merillon, C. Van Ryswick, P. Ravel, N. Benhamouda, E. Levionnois, M. Nizard, A. Si-Mohamed, N. Besnier, A. Gey, R. Rotem-Yehudar, H. Pere, T. Tran, C.L. Guerin, A. Chauvat, E. Dransart, C. Alanio, S. Albert, B. Barry, F. Sandoval, F. Quintin-Colonna, P. Bruneval, W.H. Fridman, F.M. Lemoine, S. Oudard, L. Johannes, D. Olive, D. Brasnu, E. Tartour, PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer, Cancer Res, 73 (2013) 128-138. | - |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/88282 | - |
dc.description.abstract | 在我們的研究中,我們正努力尋找新的治療策略,以提升對肝細胞癌(Hepatocellular carcinoma, HCC) 現有治療方法的效果。我們評估了新抗生原疫苗的效果,無論是單獨使用或與抗PD-1 (anti-programmed cell death protein-1,anti-PD-1) 一起使用。首先以全外顯子定序 (whole exome sequencing) 在癌細胞與正常小鼠肝臟進行了比對找出變異序列,重點是頻率較高的非同義變體 (non-synonymous mutations,NSMs)。通過RNA-seq確認了它們的表達,並分析它們的MHC-II結合親和力。排名前20的新生抗原胜肽被合成並在小鼠上進行了 IFN-γ酶聯免疫斑點 (ELIspot) 和流式細胞儀 (flow cytometry) 的測試。挑出最具免疫原性的胜肽 (immunogenic peptides) 作為疫苗,並在皮下 (subcutaneous) 、原位 (orthotopic) 和轉移性肝 (metastatic liver) 三種小鼠HCC模型進行測試。我們比較了對照組、抗PD-1組、肝癌特異性新抗原疫苗組和疫苗與抗PD-1組合組的結果。
在HCC模型中,只有通過新抗原疫苗接種和抗PD-1療法的組合才能實現腫瘤的明顯縮小,這也建立了免疫記憶。雖然新抗原疫苗接種引發了腫瘤特異性免疫反應,但它作為一種單獨的治療方法並不有效。聯合治療和疫苗接種都重塑了腫瘤微環境,增加了CD8+ T細胞和顆粒酶B的表達,同時減少了CD8+T細胞的耗竭。 NanoString分析顯示兩組的免疫細胞數量得分與免疫相關基因表達趨勢相似。然而,聯合療法獨特地減少了Treg和MDSC細胞,活化了更多的免疫途徑。此外,疫苗組在CD8+ T細胞上有最高的PD-1表達。我們假設,抗PD-1組缺乏反應可能是由於CD8+ T細胞不足,而疫苗組的無效可能是由於PD-1的高表達、MDSC細胞的抑制或其他因素阻礙了CD8+ T細胞對腫瘤的細胞毒性。 我們的新抗原疫苗是基於在Hep-55.1C和Dt81 Hepa1-6腫瘤細胞中發現的NSMs來設計的。為了降低後續分析的成本,我們對大量樣本進行了篩選和過濾。不幸的是,NSMs僅佔腫瘤細胞所有序列變異的一部分,這讓我們不得不擴大考慮範疇,考慮其他的免疫原變異,如插入和刪除 (insertions and deletions,INDELs) 以及基因融合 (gene fusions) 。由於抗原的免疫原性無法預測,蛋白質合成的高成本,以及分析過程的耗時,使得這個過程相當具有挑戰性。 在我們尋找解決方案的過程中,我們探索了各種治療策略,並認為原位免疫接種 (in Situ Vaccination,ISV) 具有前景。我們使用一種稱為poly-ICLC的疫苗佐劑 (vaccine adjuvant),這是一種TLR激動劑 (Toll-like receptor agonists),直接注射入腫瘤以啟動"免疫週期" (immune cycle) 。這種方法通過poly-ICLC刺激腫瘤部位,可能導致腫瘤細胞溶解,抗原釋放,以及抗原呈現細胞功能的增強,從而引發隨後的後天性免疫反應來攻擊腫瘤細胞。此外,這種方法的一個顯著優點是,它不需要時間來識別潛在的腫瘤抗原。 我們在Hep-55.1C細胞誘導的皮下腫瘤小鼠中測試了瘤內注射 (Intratumoral,IT) 、肌肉注射 (Intramuscular,IM) 和序列性注射 (sequential injection,先IT接著IM) poly-ICLC。聯合注射顯示出最大的腫瘤抑制作用,腫瘤浸潤的CD8+ T細胞增加了四倍,產生了強大的腫瘤特異性和全身免疫力,從而產生了遠端效應 (abscopal effect)。這一結果依賴於CD8+ T細胞,因為去除它們會導致腫瘤不受控制地生長。 總結本論文研究,新生抗原疫苗和抗PD-1治療的結合使用在治療三種不同模型的小鼠肝癌中展現出相當大的有效性。這主要是通過增強腫瘤特異性CD8+ T細胞和減少免疫抑制細胞來實現的。此外,本研究中使用的序列性poly-ICLC注射治療能明顯增加了腫瘤特異性CD8+ T細胞的數量,增強其浸潤HCC腫瘤組織中的能力並引發遠端效應。這些發現有助於推動將新生抗原疫苗與抗PD-1或採用ISV的方式將poly-ICLC用於治療HCC的臨床試驗。 | zh_TW |
dc.description.abstract | Our research aimed to identify novel therapeutic strategies to improve the efficacy of existing treatments for hepatocellular carcinoma (HCC). We evaluated the efficacy of neoantigen vaccines, both individually and in conjunction with anti-PD-1, in mouse liver cancer models of Hep-55.1C and Dt81 Hepa1-6. Firstly, whole exome sequencing (WES) was carried out in cancer cells and normal mouse liver to identify variant sequences, focusing on the higher frequency of non-synonymous mutations (NSMs). Their expression was confirmed by RNA-seq, and their MHC-II binding affinity was analyzed. Top 20 neoantigen peptides were synthesized and tested on mice using IFN-γ enzyme-linked immunospot (ELIspot) and flow cytometry. Selected the most immunogenic peptides for vaccines and tested on three HCC mouse models (subcutaneous, orthotopic, and metastatic liver tumor). We compared results among control, anti-PD-1, vaccine, and a combination group.
In HCC models, only a combination of neoantigen vaccination and anti-PD-1 therapy achieved notable tumor reduction and built immune memory. Solo vaccination-initiated tumor-specific immunity but was insufficient. Both the combined therapy and vaccination reshaped the tumor microenvironment, increasing CD8+ T cells and granzyme B expression while decreasing CD8+ T cell exhaustion. NanoString analysis revealed similar immune cell score and inflammation trends in both groups. However, the combined therapy uniquely reduced Treg and MDSC cells and activated more immune pathways. Moreover, the vaccine group had the highest PD-1 expression on CD8+ T cells. We hypothesized that the lack of response in the anti-PD-1 group might be due to inadequate CD8+ T cells, and ineffectiveness in the vaccine group could be due to high PD-1 expression, MDSC cell inhibition, or other factors hindering CD8+ T cell cytotoxicity against tumors. Our neoantigen vaccine was designed based on the unique NSMs found in Hep-55.1C and Dt81 Hepa1-6 tumor cells. To reduce subsequent analysis costs, we filtered and screened a multitude of samples. Unfortunately, the fact that NSMs made up a fraction of all sequence variations in tumor cells necessitated us to look beyond, considering other immunogenic variants like base insertions and deletions (INDELs) and gene fusions. However, the process was quite challenging due to the unpredictable immunogenicity of antigens, the high cost of protein synthesis, and the time-consuming nature of the analysis process. In our quest for a solution, we explored various therapeutic strategies and identified in situ vaccination (ISV) as promising. We used a vaccine adjuvant called poly-ICLC, which was a Toll-like receptor agonist, injecting it directly into the tumor to initiate the "immune cycle ". This approach stimulated the tumor site with poly-ICLC, potentially leading to tumor cell dissolution, antigen release, and the enhancement of antigen-presenting cell function, thereby instigating a subsequent adaptive immune response to attack the tumor cells. Moreover, a significant advantage of this method was that it did not require taking time to identify potential tumor neoantigens. We further tested if the administration method would affect poly-ICLC’s efficacy, and applied intratumoral (IT), intramuscular (IM), and sequential (IT and IM) injections in subcutaneous tumor mice induced by Hep-55.1C cells. The combined injection group showed the greatest tumor inhibition and a fourfold increase in tumor-infiltrating CD8+ T cells, generating a strong tumor-specific and systemic immunity that triggered an abscopal effect. This result relied on CD8+ T cells, as their removal led to uncontrolled tumor growth. In conclusion, the combination of neoantigen vaccination and anti-PD-1 treatment has demonstrated significant effectiveness in curing three different models of mouse liver cancer. This was primarily achieved by enhancing the presence of tumor-specific CD8+ T cells and reducing immunosuppressive cells. Furthermore, the sequential poly-ICLC treatment utilized in this study markedly increased the number of tumor-specific CD8+ T cells, thereby improving their ability to infiltrate HCC tumor tissues and triggering an abscopal effect. These findings advocated for clinical trials that combined neoantigen vaccines with anti-PD-1, or ISV with poly-ICLC, for HCC treatment. | en |
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dc.description.tableofcontents | 致謝 I
中文摘要 II 英文摘要 V 目錄 VIII 圖目錄 XV 表目錄 XIX CHAPTER 1 Introduction - 1 - 1.1 Hepatocellular carcinoma - 1 - 1.1.1 Risk factors for HCC - 2 - 1.1.2 Treatment options for early and intermediate stage HCC. - 2 - 1.1.3 Treatment of advanced HCC - 5 - 1.2 Cancer Immunotherapy - 7 - 1.2.1 Types of immunotherapies - 9 - 1.2.2 Current HCC immunotherapy - 17 - 1.3 Therapeutic cancer vaccine - 22 - 1.3.1 Principle of neoantigen vaccines - 23 - 1.3.2 Tumor-Associated Antigens (TAAs) - 28 - 1.3.3 Tumor-Specific Antigens (TSAs) - 30 - 1.3.4 In situ vaccination (ISV) - 32 - 1.3.5 poly-ICLC - 33 - Research purposes - 35 - CHAPTER 2 Materials and Methods: - 36 - 2.1 Experimental animals - 36 - 2.2 Mouse HCC cell lines - 37 - 2.3 Preparation of tissue DNA and RNA for sequencing - 37 - 2.4 Next generation sequencing - 38 - 2.5 Sequential data analysis process (Bioinformatics analysis) - 39 - 2.6 Selection and prioritization of neoantigens for peptide synthesis - 40 - 2.7 Immunogenicity testing through mouse vaccination - 41 - 2.8 Splenocyte isolation - 42 - 2.9 Evaluating Peptide Immunogenicity with IFN-γ ELIspot Assay and Flow Cytometry on Splenocytes - 42 - 2.10 Analyzing draining lymph nodes immune cells through flow cytometry. - 44 - 2.11 Establishment of mouse HCC models by different HCC cancer cell lines - 44 - 2.12 Evaluation of therapeutic effects for established HCC tumours - 46 - 2.13 Poly-ICLC treatment of established HCC tumors - 48 - 2.14 Immunofluorescence staining of tumor tissues. - 48 - 2.15 Isolation of TILs for flow cytometry analyses - 49 - 2.16 Isolation of splenocytes for in vitro killing assay - 50 - 2.17 Immune-related gene expression analysis - 51 - 2.18 Statistics - 52 - CHAPTER 3 Result: - 53 - 3.1 The metastatic liver tumor was created through intrasplenic injection by Dt81 Hepa1-6. - 53 - 3.2 Next-generation sequencing was carried out, and non-synonymous point mutations were prioritized for neoantigen peptide synthesis. - 54 - 3.3 The immunogenicity of peptide vaccines for the treatment of Dt81 Hepa1-6 tumors was studied. - 56 - 3.4 Treatment responses of established Dt81 Hepa1-6 metastatic liver tumor to neoantigen peptide vaccines were examined. - 57 - 3.5 Treatment responses of established Dt81 Hepa1-6 subcutaneous tumor to neoantigen peptide vaccines were examined. - 58 - 3.6 The response of established subcutaneous Dt81 Hepa1-6 tumors to neoantigen peptide vaccines, including the addition of anti-PD-1 and anti-VEGFR for combination therapy, was evaluated. - 60 - 3.7 A mouse HCC model based on Dt81 Hepa1-6 tumor features was developed. - 60 - 3.8 The effects of neoantigen peptide vaccines on established Dt81 Hepa1-6 metastatic liver tumors were investigated to understand their treatment responses. - 62 - 3.9 Hep-55.1C had been better suited for subcutaneous and orthotopic HCC tumor establishment than Dt81 Hepa1-6. - 63 - 3.10 Tumor neoantigens were identified and selected in the Hep-55.1C cell line. - 64 - 3.11 The immunogenicity of peptide vaccines for the treatment of Hep-55.1C was evaluated. - 65 - 3.12 Immune responses to 6PV involved neoantigen-specific and tumor-specific reactions. - 66 - 3.13 Th1 and CD8+ T cells were stimulated following 6PV immunization. - 66 - 3.14 Treatment responses of the Hep-55.1C established subcutaneous tumor models were analyzed. - 67 - 3.15 Enhanced tumor T-cell density and granzyme B levels were observed in the combination group, as determined through immunofluorescence staining. - 69 - 3.16 Immune landscape analysis was conducted in tumor tissues. - 70 - 3.17 Validation of tumor-specific CD8+ T cell cytotoxicity was performed. - 72 - 3.18 The tumor microenvironment was dissected using gene transcription trends. - 73 - 3.19 Treatment responses of the Hep-55.1C established orthotopic liver tumor model were analyzed. - 76 - 3.20 Methods to optimize the utilization of tumor antigens. - 77 - 3.21 In the pilot study, established Hep-55.1C mouse models of HCC had responded to intratumoral (IT) poly-ICLC injection treatment. - 79 - 3.22 In the pilot study, IT in combination with IM injection treatment had favorable tumor suppressive effects. - 80 - 3.23 In the pilot study, IM poly-ICLC injection was key to increasing CD8+ T-cell infiltration in the tumor. - 81 - 3.24 Tumor growth was inhibited by sequential poly-ICLC treatment. - 82 - 3.25 Increased tumor T-cell density was observed in the sequential poly-ICLC group, as determined by immunofluorescence staining. - 83 - 3.26 The treatment's effectiveness remains unaffected by the restriction of lymphocyte movement. - 84 - 3.27 Depletion of CD8+ T cells had eliminated the effect of suppressing tumor growth. - 86 - 3.28 Sequential poly-ICLC administration had induced a systemic antitumor effect. - 86 - CHAPTER 4 Discussion and perspectives: - 88 - 4.1 Hep-55.1C cells demonstrate a considerably higher tumorigenic capacity in comparison to Hepa1.6 cells. - 88 - 4.2 Strategy for the screening of candidate peptides - 89 - 4.3 Treatment for Hep-55.1C orthotopic HCC is more effective than for subcutaneous tumors. - 92 - 4.4 The control group receiving only poly-ICLC exhibits a therapeutic effect. - 93 - 4.5 Treatment with a vaccine is not useless. - 94 - 4.6 The power of combined immunotherapy was successfully to cure the tumor. - 97 - 4.7 Poly-ICLC intratumoral treatment effectively inhibits Hep-55.1C tumor growth. - 100 - 4.8 IT in combination with IM poly-ICLC therapy enhances antitumor effects in HCC. - 101 - 4.9 IT as a switch and IM treatment strategies as pushers. - 102 - 4.10 Sequential poly-ICLC therapeutic strategy generates tumor-specific CD8+ T cells and systemic immunity. - 105 - References - 170 - Table - 197 - Appendix - 198 - | - |
dc.language.iso | en | - |
dc.title | 新生抗原疫苗或原位疫苗對肝癌治療效果的研究 | zh_TW |
dc.title | Therapeutic effects of neoantigen or in situ vaccination on hepatocellular carcinoma | en |
dc.type | Thesis | - |
dc.date.schoolyear | 111-2 | - |
dc.description.degree | 博士 | - |
dc.contributor.coadvisor | 游舒涵 | zh_TW |
dc.contributor.coadvisor | Shu-Han Yu | en |
dc.contributor.oralexamcommittee | 黃麗華;賈景山;王莉芳;沈家寧 | zh_TW |
dc.contributor.oralexamcommittee | Lih-Hwa Hwang;Jean-San Chia;Li-Fang Wang ;Chia-Ning Shen | en |
dc.subject.keyword | 肝細胞癌,新生抗原,原位疫苗接種,poly-ICLC,anti-PD-1, | zh_TW |
dc.subject.keyword | HCC,neoantigen,In situ vaccination,poly-ICLC,anti-PD-1, | en |
dc.relation.page | 204 | - |
dc.identifier.doi | 10.6342/NTU202301850 | - |
dc.rights.note | 未授權 | - |
dc.date.accepted | 2023-07-24 | - |
dc.contributor.author-college | 生物資源暨農學院 | - |
dc.contributor.author-dept | 生物科技研究所 | - |
顯示於系所單位: | 生物科技研究所 |
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