Chowell et al. analyzed the HLA-I genotype of advanced cancer patients treated with immune checkpoint blockade (ICB) and found that maximum possible heterozygosity at the HLA-A, -B, and -C loci corresponded with improved survival compared with homozygosity in at least one HLA locus. In melanoma patients, HLA-B44 supertype corresponded with prolonged survival, while HLA-B62 was associated with poor outcome. TCR clonality in the tumor tracked with HLA heterozygosity, providing a direct link between HLA genotype and diversity of T cell responses.

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-PD-1 or anti-CTLA-4 is currently unknown. We determined the HLA-I genotype of 1,535 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 to 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 unique 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.

Author Info: (1) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer

Author Info: (1) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065. USA. (2) Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065. USA. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) NewYork-Presbyterian/Columbia University Medical Center, 177 Fort Washington Ave., New York, NY 10032, USA. (4) IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA. (5) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065. USA. (6) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065. USA. (7) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065. USA. (8) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065. USA. (9) The Rockefeller University, New York, NY 10065, USA. (10) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065. USA. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (11) Tisch Cancer Institute, Departments of Medicine, Oncological Sciences, and Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. (12) David Geffen School of Medicine at UCLA, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA. (13) David Geffen School of Medicine at UCLA, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA. (14) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell School of Medicine, New York, NY 10065, USA. (15) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (16) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (17) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (18) IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA. Deartment of Chemistry, Columbia University, New York, NY 10027, USA. (19) NewYork-Presbyterian/Columbia University Medical Center, 177 Fort Washington Ave., New York, NY 10032, USA. chant@mskcc.org nar2144@cumc.columbia.edu. (20) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. chant@mskcc.org nar2144@cumc.columbia.edu. Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065. USA. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell School of Medicine, New York, NY 10065, USA.

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