Cancer epigenetics and effector T cells in immunotherapy and chemotherapy.

Abstract

17 Background: The tumor microenvironment is comprised of immune cells that have been reprogrammed by active tumor-mediated processes to defeat tumor-specific immunity and promote tumor growth in a highly effective manner. Previous studies have helped define the nature of immune responses in the tumor microenvironment, and provide new insights into designing novel immune therapies to target the immune suppressive mechanisms including Tregs and inhibitory B7 family members (e.g. PD-L1/PD-1) and treat patients with cancer. However, the mechanisms controlling tumor immune phenotype and biological phenotype, and their relevance in cancer therapy are not well understood. Methods: Using human colon and ovarian cancer as our models, we have studied the cross-talk between immune cell subsets and tumor/stem cells, and between immunogenic and oncogenic pathways in the tumor microenvironment, and its impact on tumor immunity and therapy. Results: In patients with colon and ovarian cancer as our models, we demonstrate that Th22 cells and myeloid derived suppressor cells (MDSCs) regulate tumor stemness via epigenetic mechanisms. Furthermore, we found that histone modification and DNA methylation repress the tumor production of Th1-type chemokines, and subsequently determine effector T cell trafficking to the tumor microenvironment, affect tumor progression, and therapeutic efficacy of checkpoint blockade and adoptive T cell transfusion, chemotherapy and patient outcome. Conclusions: Epigenetic silencing of Th1-type chemokine is a novel tumor immune evasion mechanism. Selective epigenetic reprogramming alters T cell landscape in cancer and may enhance clinical efficacy of cancer therapy.