Density of immunogenic antigens does not explain the presence or absence of the T-cell-inflamed tumor microenvironment in melanoma.
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.
Department of Pathology, University of Chicago, Chicago, IL 60637.
Stefani
0000-0003-3257-4546
S
Spranger
Department of Medicine, University of Chicago, Chicago, IL 60637.
Jason J
JJ
Luke
Center for Research Informatics, University of Chicago, Chicago, IL 60637.
Riyue
R
Bao
Human Immune Monitoring Facility, University of Chicago, Chicago, IL 60637.
Yuanyuan
Y
Zha
Center for Research Informatics, University of Chicago, Chicago, IL 60637.
Kyle M
KM
Hernandez
Center for Research Informatics, University of Chicago, Chicago, IL 60637.
Yan
Y
Li
Center for Research Informatics, University of Chicago, Chicago, IL 60637.
Alexander P
AP
Gajewski
Center for Research Informatics, University of Chicago, Chicago, IL 60637.
Jorge
J
Andrade
Department of Pathology, University of Chicago, Chicago, IL 60637; tgajewsk@medicine.bsd.uchicago.edu.|Department of Medicine, University of Chicago, Chicago, IL 60637.|Human Immune Monitoring Facility, University of Chicago, Chicago, IL 60637.
Thomas F
TF
Gajewski
D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology*; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000502:physiology*; D059016:Tumor Microenvironment
D000951:Antigens, Neoplasm; D015234:HLA-A Antigens
T-cell inflammation; checkpoint blockade; immunotherapy; neoantigens; tumor microenvironment