文章基本信息

标题：Density of immunogenic antigens does not explain the presence or absence of the T-cell–inflamed tumor microenvironment in melanoma
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作者：Stefani Spranger ; Jason J. Luke ; Riyue Bao 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：E7759-E7768
DOI：10.1073/pnas.1609376113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe T-cell-inflamed tumor microenvironment correlates with efficacy of immunotherapy. It is critical to understand whether non-T-cell-inflamed tumors lack antigens for T-cell recognition. In melanoma, no difference between inflamed and noninflamed tumors for multiple antigen classes was observed. Synthesized peptides corresponding to predicted HLA-A2 binding epitopes showed no differences between inflamed and noninflamed tumors. Extrapolation of a T-cell signature across The Cancer Genome Atlas showed no correlation between gene expression and mutational burden in any cancer type. These results indicate that lack of spontaneous immune infiltration in solid tumors is unlikely to be due to lack of antigens. Rather, transcriptional profiling suggests lack of Batf3-lineage dendritic cells. Our data suggest that strategies to restore T-cell entry into noninflamed tumors should be developed. Melanoma metastases can be categorized by gene expression for the presence of a T-cell-inflamed tumor microenvironment, which correlates with clinical efficacy of immunotherapies. T cells frequently recognize mutational antigens corresponding to nonsynonymous somatic mutations (NSSMs), and in some cases shared differentiation or cancer-testis antigens. Therapies are being pursued to trigger immune infiltration into non-T-cell-inflamed tumors in the hope of rendering them immunotherapy responsive. However, whether those tumors express antigens capable of T-cell recognition has not been explored. To address this question, 266 melanomas from The Cancer Genome Atlas (TCGA) were categorized by the presence or absence of a T-cell-inflamed gene signature. These two subsets were interrogated for cancer-testis, differentiation, and somatic mutational antigens. No statistically significant differences were observed, including density of NSSMs. Focusing on hypothetical HLA-A2+ binding scores, 707 peptides were synthesized, corresponding to all identified candidate neoepitopes. No differences were observed in measured HLA-A2 binding between inflamed and noninflamed cohorts. Twenty peptides were randomly selected from each cohort to evaluate priming and recognition by human CD8+ T cells in vitro with 25% of peptides confirmed to be immunogenic in both. A similar gene expression profile applied to all solid tumors of TCGA revealed no association between T-cell signature and NSSMs. Our results indicate that lack of spontaneous immune infiltration in solid tumors is unlikely due to lack of antigens. Strategies that improve T-cell infiltration into tumors may therefore be able to facilitate clinical response to immunotherapy once antigens become recognized.
关键词：checkpoint blockade ; neoantigens ; immunotherapy ; T-cell inflammation ; tumor microenvironment