Project 3: Genetic and epigenetic basis of resistance to RT and ICB

Wherry, E.

Abstract

Resistance to Immune Checkpoint Blockade (ICB) and failure to develop durable immunity after partial responses may occur through intrinsic or acquired mechanisms. Mechanistic details and clinical correlates on how cancer escapes ICB are lacking. In previous work, we discovered that resistance to combination ICB therapy consisting of radiation (RT) and anti-CTLA4 can occur with upregulation of PDL1. This is associated with increased expression of interferon-stimulated genes (ISGs). Our preliminary data reveal a key role for tumor-intrinsic resistance mechanisms driven by prolonged interferon (IFN) signaling and related to tumor burden. Moreover, recent clinical results define a link between tumor burden and efficacy of ICB revealed by changes in exhausted T cells (TEX). We have found critical transcriptional and epigenetic events in both tumor cells and responding TEX that may reveal PDL1-independent mechanisms of resistance that are driven by prolonged IFN signaling and tumor burden. To complement parallel clinical trials that test the combination of RT + ?CTLA4 + ?PD1 in patients with advanced cancer, this project seeks to investigate PDL1-independent resistance mechanisms by examining both tumor cells and T cells. We will test the hypothesis that tumor burden and prolonged IFN signaling lead to reciprocal genomic/epigenomic changes in both cell types that limit the efficacy of RT + ?CTLA4 + ?PDL1/PD1, and that the reversibility of these genomic/epigenomic changes impacts the efficacy and durability of responses. By integrating pre-clinical and clinical efforts, our goal is to understand how IFN, a major signal in the tumor microenvironment, can paradoxically drive additional but targetable immune checkpoint pathways to control T cell exhaustion and resistance to combination therapy. In so doing, we will inform the design of the next generation of clinical trials by focusing on underlying determinants of durable response.

Public Health Relevance

Immunotherapies including checkpoint blockade are transforming cancer treatments, but the majority of patients do not achieve robust and durable responses. Combining immune checkpoint blockade (ICB) with radiation (RT) has improved responses, but we do not understand the underlying mechanisms and many patients still progress. Based on pre-clinical and clinical evidence, we have described a PDL1 circuit, likely linked to IFN signaling, acting as a dominant resistance mechanism to ICB + RT. Here we will test how overall tumor burden and prolonged IFN signaling drive PD-L1-independent resistance pathways, and define the genomic/epigenomic changes in tumor cells and T cells, that will provide the next generation of immunotherapy targets to increase the efficacy and durability of responses.