探討口腔鱗狀上皮細胞癌中表現 B7-H1和PD-1之浸潤T淋巴球

Abstract

在口腔中超過95%的惡性腫瘤為口腔鱗狀上皮細胞癌，並且為台灣六大常見侵襲癌症死因之ㄧ。人類產生在不同器官或組織的癌症，其疾病起因除了基因毒性和致癌基因突變外，免疫編輯(immune-editing)也被視為一個重要的因素，目前已經有研究指出調節性T細胞(Tregs)和表現抑制性B7分子的細胞對於腫瘤微環境的免疫抑制以及腫瘤生長都有貢獻。在本論文中發現口腔癌腫瘤組織抑制性B7-H1分子和調節性T細胞的表現相關性，接著分析口腔癌病人表現抑制性B7-H1分子的腫瘤浸潤調節性T細胞。研究發現腫瘤組織CD4+CD25+Foxp3+調節性T細胞有88.08%表現B7-H1，比起病人PBMC(64.71%)(p= 0.001)和正常人PBMC (73.78%) (p=0.04)都高出許多，並且發現腫瘤組織B7-H1+Foxp3+和Foxp3+細胞之百分比在TIL呈現中度相關(r=0.61)，而在CD4+ T細胞內則是呈現高度相關(r=0.75)。TIL內CD4+ CD25+Foxp3-活化T細胞之B7-H1接受體PD-1(programmed death-1)的平均表現螢光表現強度大約是PBMC的六倍高，CD4+CD25-Foxp3-未活化T細胞在TIL大約是PBMC的五倍高，然而CD4+CD25+Foxp3+調節性T在TIL大約只有PBMC的二倍高，並且發現B7-H1+Foxp3+表現百分比和PD-1表現強度在腫瘤組織CD4+T 細胞(r=0.6)具有中度相關性。此外在組織免疫染色也發現，口腔癌腫瘤組織中有Foxp3+ B7-H1+、Foxp3+ B7-H1-和PD-1+的浸潤T細胞。因此本論文發現有表現共同抑制性B7-H1分子的調節性T細胞亞群，浸潤於口腔鱗狀上皮細胞癌中，並且可能是藉由和PD-1的結合而具有免疫調節的功能。

Oral squamous cell carcinoma(OSCC) accounts for over 90% of the oral malignant neoplasms, ranks as the sixth major cause of cancer mortality rate in Taiwan and the incidence rate is raising. In addition to mutation of oncogene and gene toxicity, the cancer immune-editing is one of the important factors in human cancer currently. The regulatory T cell and high levels of expression of coinhibitory B7 molecules are the mediators of immunosuppression in tumor microenviriment. Therefore, we investigated the relationship of B7-H1 and regulatory T cells in human oral squamous cell carcinoma.The results indicate that, in TIL, proportion of distinct CD25+ Foxp3+ cells in the CD4+ subset (88.08%) were enriched relative to that found in PBMC (64.71 %) from OSCC patients(p= 0.001)and PBMC(73.78%) from healthy donor (p=0.04).The linear correction analysis indicated that Foxp3+ and B7-H1+Foxp3+ Tregs were positively correlated in TIL(R=0.61) and CD4+ T cell(R=0.75). The PD-1 (the receptor of B7-H1) average expression on CD4+CD25-Foxp3- and CD4+CD25+ Foxp3- in TIL is five- or six-fold to PBMC , but it is only two fold in CD4+CD25+ Foxp3+ regulatory T cell. The linear analysis indicated that PD-1 average expression and proportion of B7-H1+Foxp3+ Tregs on CD4+T cell were positively correlated (R=0.60).Furthermore, we also observe the B7-H1+ Foxp3+Tregs and PD-1+ T cell in the immunohistochemistry. Therefore, B7-H1+Tregs and PD-1+ T cell infiltrated in tumor may play a immunoregulatory role in oral squamous cell carcinoma.