Deciphering the epigenetic programming underlying CD8 T cell dysfunction in solid tumors

Abstract

Abstract Tumor-specific CD8 T cells in progressive solid tumors express inhibitory receptors and fail to proliferate and produce effector cytokines. Using a mouse model (ASTxCre-ERT2) in which tamoxifen (TAM) treatment induces an oncogenic driver neoantigen, SV40 large T antigen (Tag) in hepatocytes, we previously showed that tumor-specific CD8 T cells (TCRSV40-I) become unresponsive quite early during the pre-/early malignant phase. While the dysfunctional state is initially plastic, TCRSV40-I cells soon enter a fixed dysfunctional state with the phenotypic, functional, and molecular hallmarks of T cells from late-stage human tumors. To define the epigenetic programs associated with plasticity and imprinting of tumor-specific T cell dysfunction, we used the “Assay for Transposase-Accessible Chromatin using Sequencing” (ATAC-Seq) to map chromatin accessibility in TCRSV40-I cells isolated from pre/early malignant lesions as well as in TCRSV40-I differentiating to the normal effector and memory states. Chromatin accessibility changes underlying TCRSV40-I activation and differentiation in pre-malignant lesions diverged from that in normal differentiation, and we observed 2 distinct chromatin accessibility patterns in dysfunctional TCRSV40-I correlating with the plastic and fixed dysfunctional states. Surprisingly, memory TCRSV40-I transferred into mice with late-stage established Tag-expressing hepatocellular carcinomas displayed these same 2 chromatin accessibility profiles, thus regardless of the initial CD8 T cell epigenetic state, epigenetic remodeling drives tumor-specific T cell differentiation to the dysfunctional state in both pre-malignant lesions and late established solid tumors.