MHC-I genotype and tumor mutational burden predict response to immunotherapy

Genome Medicine

Xinlian Zhang¹  Edward D. Ball²  Aaron M. Goodman²  Razelle Kurzrock³  Shumei Kato³  Paul Riviere³  Ryosuke Okamura³  Hannah Carter⁴  Rachel Marty Pyke⁴  Andrea Castro⁴  Ethan Sokol⁵  Garrett Frampton⁵ 

[1] Division of Biostatistics and Bioinformatics, Department of Family Medicine and Public Health, University of California San Diego;Division of Blood and Marrow Transplantation, Department of Medicine, University of California San Diego;Division of Hematology/Oncology Center for Personalized Cancer Therapy, Department of Medicine, University of California San Diego;Division of Medical Genetics, Department of Medicine, University of California San Diego;Foundation Medicine;

关键词: MHC-I;    TMB;    Biomarkers;    Checkpoint blockade;   

DOI  :  10.1186/s13073-020-00743-4

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown