Journal Article

Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy

Riaz, Nadeem, Samstein, Robert M., Berger, Michael, Chan, Timothy A., Kuo, Fengshen, Requena, David, Kendall, Sviatoslav M., Greenbaum, Benjamin, Chowell, Diego, Zhou, Ruhong, Rizvi, Naiyer A., Solit, David, Zehir, Ahmet, Weber, Jeffrey K., Garon, Edward, Grigg, Claud M., Carroll, James, Makarov, Vladimir, Morris, Luc G. T., Hyman, David M.

2018

Overview

Immunotherapy works by activating the patient's own immune system to fight cancer. For effective tumor killing, CD8 + T cells recognize tumor peptides presented by human leukocyte antigen class I (HLA-I) molecules. In humans, there are three major HLA-I genes ( HLA-A, HLA-B , and HLA-C ). Chowell et al. asked whether germline HLA-I genotype influences how T cells recognize tumor peptides and respond to checkpoint inhibitor immunotherapies (see the Perspective by Kvistborg and Yewdell). They examined more than 1500 patients and found that heterozygosity at HLA-I loci was associated with better survival than homozygosity for one or more HLA-I genes. Thus, specific HLA-I mutations could have implications for immune recognition and for the design of epitopes for cancer vaccines and immunotherapies. Science , this issue p. 582 ; see also p. 516 Human leukocyte antigen superfamilies predict immunotherapy response. 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.

• Publisher: The American Association for the Advancement of Science
• Subject: Adult / Aged / Antigen (tumor-associated) / Antigen Presentation / Antigens / Antigens, Neoplasm - immunology / Apoptosis / Cancer / Cancer vaccines / Cancer Vaccines - immunology / Cancer Vaccines - therapeutic use / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Cell death / Cell recognition / Cohort Studies / CTLA-4 Antigen - antagonists & inhibitors / Cytotoxicity / Epitopes / Genes / Genetic Carrier Screening / Genotype & phenotype / Genotypes / Heterozygosity / Histocompatibility antigen HLA / Histocompatibility Antigens Class I - chemistry / Histocompatibility Antigens Class I - genetics / Homozygosity / Humans / Immune checkpoint / Immune system / Immunotherapy / Immunotherapy - methods / Leukocytes / Loci / Loss of heterozygosity / Lymphocytes / Lymphocytes T / Melanoma / Melanoma - genetics / Melanoma - immunology / Melanoma - mortality / Melanoma - therapy / Middle Aged / Molecular dynamics / Mutation / Neoantigens / Patients / Peptides / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Protein Conformation / Recognition / Skin Neoplasms - genetics / Skin Neoplasms - immunology / Skin Neoplasms - mortality / Skin Neoplasms - therapy / Survival / Treatment Outcome / Tumors / Vaccines / Young Adult