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Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):E7759-E7768. Epub 2016 Nov 11.

Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma.

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Department of Pathology, University of Chicago, Chicago, IL 60637.
Department of Medicine, University of Chicago, Chicago, IL 60637.
Center for Research Informatics, University of Chicago, Chicago, IL 60637.
Human Immune Monitoring Facility, University of Chicago, Chicago, IL 60637.
Department of Pathology, University of Chicago, Chicago, IL 60637;


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.


T-cell inflammation; checkpoint blockade; immunotherapy; neoantigens; tumor microenvironment

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