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

Aaron M Goodman,Ethan Sokol,Andrea Castro,Rachel Marty Pyke,Hannah Carter,Garrett Frampton,Edward D Ball,Shumei Kato,Xinlian Zhang,Ryosuke Okamura,Paul Riviere,Razelle Kurzrock

doi:10.1186/s13073-020-00743-4

Abstract

BackgroundImmune 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.MethodsComprehensive 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.ResultsThe 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.ConclusionsPoor presentation of driver mutation neoantigens by MHC-I may explain why some tumors (even with a high TMB) do not respond to ICB.

Highlights

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
It has been suggested that the presence of a highquality neoantigen is required for response to therapy [32] while a high burden of neoantigens has been associated with impaired anti-tumor immune activity [33]; we focused on neoantigen quality over quantity by using patient minimum Patient Harmonic-mean Best Rank (PHBR) score to predict whether mutations observed in a patient’s tumor are likely to generate effectively presented neoantigens
A minimum PHBR score ≥ 0.5 was significantly associated in univariate analysis with progressive disease (P = 0.02), non-cutaneous squamous cell carcinoma (SCC) malignancies (P = 0.04), and a tumor mutational burden (TMB) < 50 mutations/mb (P = 0.05)

Summary

Introduction

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. 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. 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 has revolutionized the treatment of both solid [1] and hematologic malignancies [2]. Multiple factors influence the immune response against tumors including tumor T cell infiltration, tumor mutational burden (TMB), PD-L1 expression, interferon signaling, mismatch repair (MMR) deficiency, tumor aneuploidy, and possibly the intestinal microbiota [10]. Biomarkers that have entered clinical practice include PD-L1 expression measured by immunohistochemistry (IHC) [11], PD-L1 amplification [12], microsatellite instability (MSI) [13, 14], and TMB [15, 16]

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Conclusion