Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 48, Pages E7759-E7768Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1609376113
Keywords
checkpoint blockade; neoantigens; immunotherapy; T-cell inflammation; tumor microenvironment
Categories
Funding
- National Cancer Institute (NCI) [K99CA204595]
- Paul Calabresi Career Development in Clinical Oncology Award [NIH 1K12CA139160-05]
- Young Investigator Award from the Cancer Research Foundation
- Arthur J. Schreiner Family Melanoma Research Fund
- Center for Research Informatics of the University of Chicago Biological Science Division
- Institute for Translational Medicine/Clinical and Translational Award [NIH UL1 RR024999]
- Bristol Myers Squibb
- NCI [R01CA198496]
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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.
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