Abstract P054: Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types

The FDA has recently approved a high tumor mutational burden (TMB-High, defined by ≥10 mutations/Mb) as a biomarker for the treatment of advanced solid tumors with pembrolizumab, an immune checkpoint inhibitor (ICI) that targets PD1. However, recent studies have shown that this TMB-high biomarker is only able to stratify ICI responders in a subset of cancer types, where the mechanisms underlying this observation have remained unknown. We hypothesized that the tumor immune microenvironment (TME) may determine the ability of high-TMB to stratify responders of ICI (termed TMB power) in each cancer type. To systematically study this hypothesis, we first inferred the levels of 31 immune-related factors characteristic of the TME of different cancer types in the TCGA. We next integrated this information with a cohort of 2,277 ICI-treated patients with TMB and response measures, to identify the key immune factors that can determine TMB power across 14 different cancer types. This cohort was created by collating the largest publicly available cohort comprising 1959 patients together with a new cohort of 318 patients, where TMB has been quantified using the MSK-IMPACT panel. We find that high levels of M1 macrophages and low levels of resting dendritic cells in the TME characterize cancer types with high TMB power. These findings are aligned with prior reports that M1 macrophages could be anti-tumorigenic by fostering an inflammation response and activating CD8 T cells against tumor, and that resting dendritic cells may induce tolerance to tumor antigens via inducing T cell death or their anergic state. A model based on these two immune factors strongly predicts TMB power across cancer types (Spearman Rho=0.76, P<3.6E-04). Using this model, we provide predictions of the TMB power in nine additional cancer types, including rare cancers, for which TMB and ICI response data are not yet publicly available on a large scale. These predictions can be used to prioritize the clinical trials testing the usage of TMB-high biomarker in new cancer types. In this line, our analysis indicates that TMB-High may be strongly predictive of ICI response in cervical squamous cell carcinoma, suggesting that such a study should be prioritized.

Citation Format: Neelam Sinha, Sanju Sinha, Christina Valero, Alejandro A. Schaffer, Kenneth Aldape, Kevin Litchfield, Timothy A. Chan, Luc G. T. Morris, Eytan Ruppin. Immune determinants of the association between tumor mutational burden and immunotherapy response across cancer types [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P054.