We have studied the cross-talk between immune cell subsets and tumor/stem cells in the human tumor microenvironment and its impact on tumor immunity and therapy. Our prior research efforts demonstrate that 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. These studies have helped define the nature of immune responses in the tumor microenvironment; provide original insights into designing 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. Using several human cancers as our models, we demonstrate that Th22 cells and myeloid derived suppressor cells (MDSCs) and macrophages regulate tumor EMT and 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—affecting tumor progression, therapeutic efficacy of checkpoint blockade and adoptive T cell transfusion, and patient outcome. Thus, epigenetic mechanisms determine tumor immune phenotype (hot vs cold) and tumor biological phenotype (EMT/stem-like vs non EMT/stem like) and shape immunotherapy response. In addition to immunotherapy, we found that effector T cells affect chemoresistance. CD8+ T cells abolish ovarian cancer cisplatin-resistance by altering glutathione and cystine metabolism in fibroblasts. CD8+ T cell-derived IFNγ controls fibroblast glutathione and cysteine through up-regulation of gamma-glutamyl transpeptidase and transcriptional repression of system xc− cystine and glutamate antiporter via the JAK/STAT1 pathway. Thus, effector T cells play a role in cancer chemoresistance. Selective epigenetic reprogramming may alter T cell landscape in cancer and enhance clinical efficacy of cancer immunotherapy and chemotherapy.
Citation Format: Weiping Zou. Cancer epigenetic and metabolic mechanisms controlling immunotherapy and chemotherapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA28.
- ©2016 American Association for Cancer Research.