Abstract B28: Targeting TBK1 to overcome resistance to cancer immunotherapy

Abstract Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. We identified the innate immune kinase TANK-binding kinase 1 (TBK1) as a candidate immune evasion gene in a pooled genetic screen. Using a suite of genetic and pharmacologic tools across multiple experimental model systems, we confirm a role for TBK1 as an immune evasion gene. Targeting TBK1 enhances response to PD-1 blockade by lowering the cytotoxicity threshold to effector cytokines (TNF𝛂/IFN𝛄). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumor models, with concordant findings in matched patient-derived organotypic tumor spheroids (PDOTS) and matched patient-derived organoids (PDOs). Tumor cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF𝛂/IFN𝛄 in a JAK/STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy. Citation Format: Yi Sun, Or-yam Revach, Seth Anderson, Robert T. Manguso, Russell W Jenkins. Targeting TBK1 to overcome resistance to cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B28.