MHC-I genotype and tumor mutational burden predict response to immunotherapy. Genome Med 2020 May 19;12(1):45
Date
05/21/2020Pubmed ID
32430031Pubmed Central ID
PMC7236948DOI
10.1186/s13073-020-00743-4Scopus ID
2-s2.0-85084962181 (requires institutional sign-in at Scopus site) 68 CitationsAbstract
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.
Author List
Goodman AM, Castro A, Pyke RM, Okamura R, Kato S, Riviere P, Frampton G, Sokol E, Zhang X, Ball ED, Carter H, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antigens, NeoplasmAntineoplastic Agents, Immunological
Female
Genotype
Histocompatibility Antigens Class I
Humans
Immunotherapy
Male
Middle Aged
Mutation
Neoplasms
Survival Analysis
