Title
Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy
Date Issued
02 February 2018
Access level
open access
Resource Type
journal article
Author(s)
Chowell D.
Morris L.G.T.
Grigg C.M.
Weber J.K.
Samstein R.M.
Makarov V.
Kuo F.
Kendall S.M.
Riaz N.
Greenbaum B.
Carroll J.
Garon E.
Hyman D.M.
Zehir A.
Solit D.
Berger M.
Zhou R.
Rizvi N.A.
Chan T.A.
Rockefeller University
Publisher(s)
American Association for the Advancement of Science
Abstract
CD8+ T cell–dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti–programmed cell death protein 1 or anti–cytotoxic T lymphocyte–associated protein 4 is currently unknown. We determined the HLA-I genotype of 1535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci (“A,” “B,” and “C”) improved overall survival after ICB compared with patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed different elements that may impair CD8+ T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.
Start page
582
End page
587
Volume
359
Issue
6375
Language
English
OCDE Knowledge area
Inmunología
Scopus EID
2-s2.0-85037700703
PubMed ID
Source
Science
ISSN of the container
0036-8075
Sponsor(s)
Data reported in this study are tabulated in the main text and supplementary materials. This work was supported by NIH/National Cancer Institute Cancer Center Support Grant P30 CA008748, NIH grant K08 DE024774 (L.G.T.M), Damon Runyon Cancer Research Foundation (L.G.T.M), Pershing Square Sohn Cancer Research Alliance (T.A.C), STARR Cancer Consortium (T.A.C), Stand Up 2 Cancer (T.A.C), and NIH grant 1R01CA205426 (N.A.R and T.A.C). T.A.C. is a cofounder of Gritstone Oncology. We thank the Chan laboratory and members of the Bristol-Myers Squibb (BMS) biomarker team for helpful and stimulating discussions. We thank all the patients for their participation in the clinical trials, which is critical to improving care. We thank members of the melanoma service at MSK, including J. Wolchok, A. Shoushtari, M. Postow, and M. Callahan for their care of clinical trial patients. We thank members of the Columbia University oncology team for their excellent care of trial patients. We thank J. Sims, J. Havel, Y. Shen, and R. Srivastava for very stimulating discussions and helpful suggestions. We thank the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Cycle for Survival, and members of the Molecular Pathology and Diagnostics for their help with MSK-IMPACT sequencing. The data are available at the following accession numbers: dbGAP, phs001041.v1.p1; dbGAP, phs000452.v2.p1; SRA, SRP067938 and SRP090294; dbGAP, phs000980.v1.p1; SRA, PRJNA419415, PRJNA419422, and PRJNA419530; cBioPortal for Cancer Genomics, http://cbioportal.org/ msk-impact (37). The results published here are in part based on data generated by a TCGA pilot project established by the National Cancer Institute and National Human Genome Research Institute. Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http:// cancergenome.nih.gov. T.A.C. receives research funding from BMS. N.A.R. is a consultant/advisory board member for AstraZeneca, BMS, Roche, Merck, Novartis, Lilly, and Pfizer. T.A.C. and N.A.R are cofounders of Gritstone Oncology.
Sources of information:
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