Abstract B35: Epitope-binding promiscuity of HLA class I molecules shapes the efficacy of checkpoint blockade immunotherapy

Abstract

Abstract Immune checkpoint inhibitors (ICI), which target inhibitory receptors on T cells and thereby promote antitumor immune responses, have achieved considerable success in clinical care against a range of cancer types. However, only a subset of patients responds adequately to ICI-based immunotherapies. Therefore, it is of utmost importance to understand the immunologic mechanisms underlying resistance and adverse effects. It has been previously shown that certain MHC class I molecules are capable of promiscuous peptide binding, as they are associated with a much wider range of epitopes than others. The functional implications of such an elevated epitope-binding repertoire on the efficacy of cancer immunotherapy are unknown. In this work, we examine HLA genotypes of individuals receiving checkpoint blockade immunotherapy using two published cohorts. We demonstrate that cancer patients carrying HLA class I alleles with promiscuous peptide binding display significantly worse prognosis after ICI immunotherapy. This association remains significant after controlling for tumor types, mutational burden, and HLA genetic diversity. We also found that cancer samples of patients carrying highly promiscuous HLA class I alleles display significantly reduced expression of PD1 and CTLA-4 receptors, important markers of T-cell activation in the tumor microenvironment. Moreover, such promiscuous HLA alleles bind neoepitopes with reduced affinity. These findings indicate that high promiscuity is suboptimal due to a reduced specificity of epitope binding, yielding inadequate antitumor immune response. Citation Format: Máté Manczinger, Gergő Balogh, Balázs Koncz, Lajos Kemény, Balázs Papp, Csaba Pál. Epitope-binding promiscuity of HLA class I molecules shapes the efficacy of checkpoint blockade immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B35.