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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.

Author information

1
Department of Pathology, University of Chicago, Chicago, IL 60637.
2
Department of Medicine, University of Chicago, Chicago, IL 60637.
3
Center for Research Informatics, University of Chicago, Chicago, IL 60637.
4
Human Immune Monitoring Facility, University of Chicago, Chicago, IL 60637.
5
Department of Pathology, University of Chicago, Chicago, IL 60637; tgajewsk@medicine.bsd.uchicago.edu.

Abstract

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.

KEYWORDS:

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

PMID:
27837020
PMCID:
PMC5137753
DOI:
10.1073/pnas.1609376113
[Indexed for MEDLINE]
Free PMC Article

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