期刊
GENOME MEDICINE
卷 12, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13073-020-00743-4
关键词
MHC-I; TMB; Biomarkers; Checkpoint blockade
资金
- National Cancer Institute [P30 CA023100]
- Joan and Irwin Jacobs Fund philanthropic fund
- NIH [TL1TR001443, DP5-OD017937]
- CIFAR fellowship
- Mark Foundation for Cancer Research [18-022-ELA]
- NIH National Library of Medicine training grant [T15LM011271]
- Geoffrey Beene Cancer Research Center
- Society for Memorial Sloan Kettering Cancer Center
- Lung Cancer Research Foundation
- Frederick Adler Chair Fund
- One Ball Matt Memorial Golf Tournament
- Queen Wilhelmina Cancer Research Award
- STARR Foundation
- Ludwig Trust
- Stand Up To Cancer-Cancer Research Institute Cancer Immunology Translational Cancer Research Grant
Background Immune checkpoint blockade (ICB) with antibodies inhibiting cytotoxic T lymphocyte-associated protein-4 (CTLA-4) and programmed cell death protein-1 (PD-1) (or its ligand (PD-L1)) can stimulate immune responses against cancer and have revolutionized the treatment of tumors. The influence of host germline genetics and its interaction with tumor neoantigens remains poorly defined. We sought to determine the interaction between tumor mutational burden (TMB) and the ability of a patient's major histocompatibility complex class I (MHC-I) to efficiently present mutated driver neoantigens in predicting response ICB. Methods Comprehensive genomic profiling was performed on 83 patients with diverse cancers treated with ICB to determine TMB and human leukocyte antigen-I (HLA-I) genotype. The ability of a patient's MHC-I to efficiently present mutated driver neoantigens (defined by the Patient Harmonic-mean Best Rank (PHBR) score (with lower PHBR indicating more efficient presentation)) was calculated for each patient. Results The median progression-free survival (PFS) for PHBR score < 0.5 vs. >= 0.5 was 5.1 vs. 4.4 months (P = 0.04). Using a TMB cutoff of 10 mutations/mb, the stable disease > 6 months/partial response/complete response rate, median PFS, and median overall survival (OS) of TMB high/PHBR high vs. TMB high/PHBR low were 43% vs. 78% (P = 0.049), 5.8 vs. 26.8 months (P = 0.03), and 17.2 months vs. not reached (P = 0.23), respectively. These findings were confirmed in an independent validation cohort of 32 patients. Conclusions Poor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.
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