以系統性全癌分析探討腫瘤突變與腫瘤微環境的關係

Abstract

隨著免疫療法的進展，許多療法都有相當大的進展。但是這些療法的成效受到癌症腫瘤所創造出的微環境很大的影響，為了瞭解癌症腫瘤微環境裡面，腫瘤和周遭的免疫細胞的交互作用，在本研究中我們根據TCGA中腫瘤樣本裡免疫和基質細胞的組成，來重新將癌症腫瘤分成四種免疫亞型：分別為發炎型(S1)、毒殺細胞型(S2)、淋巴細胞耗竭型(S3)以及中性粒細胞型(S4)。我們分別探討了這四種免疫亞型的各種特性，包含：基因變異、免疫調節基因、病人預後等等。我們發現淋巴細胞耗竭型有較差的預後，而毒殺細胞型有較好的預後且有很高的突變負荷。我們還另外發現了一些特定已知的主導基因，例如BRAF 和CTNNB1 (和免疫細胞排除有關)的突變有分別顯著出現在發炎型和淋巴細胞耗竭型，另外還有TP53、TGFBR2和KRAS的突變顯著出現在中性粒細胞型。透過分析33種癌症的腫瘤樣本，我們找出和腫瘤微環境有關的基因突變以及變異的生物路徑。根據這些結果，我們希望有助於深入了解哪些異常突變會影響不同腫瘤微環境的形成。

With the advent of immunotherapy, it is essential to understand the interactions between tumors and cells in the tumor microenvironment. We estimated the abundance of ten im-mune and two stromal cell populations in all TCGA tumor samples from transcriptomic data. Based on the microenvironment composition across all tumor types, we identified four consensus immune subtypes: (S1) inflammatory, (S2) cytotoxic dominant, (S3) lymphocyte depleted, and (S4) neutrophil dominant. The four immune subtypes were further characterized by mutation, expression of immunomodulatory genes, and prognosis. The lymphocyte-depleted subtype had less favorable outcomes, while cytotoxic-dominant subtype had a better prognosis and higher average mutation load. Specific driver genes correlated with immune subtypes, such as BRAF and CTNNB1 mutations were observed over-representatively in high and low leukocyte-infiltrating subtypes S1 and S3, respec-tively, where CTNNB1 has been demonstrated that its activation is correlated with immune exclusion. In addition, TP53, TGFBR2, and KRAS mutations are significantly enriched in the neutrophil dominant subtype. In this study, we analyzed data with 33 diverse cancer types to identify the tumor micro-environment-associated genes and related dysfunctional pathways. The results provide insight into how genetic aberration shapes the tumor microenvironment.