Immune-Associated Epigenetic Regulation in the Tumor Microenvironment

[摘要] The tumor consists of a microenvironment of many cells, including stromal and immune cells. The immune system not only can eliminate tumor cells but also can promote tumorigenesis.The tumor is constantly evolving with the pressure of the immune response and eventually creates an immunosuppressive environment and recruits immune cells that can promote its growth. This dissertation focuses on the tumor-immune crosstalk, both the effect of T cells on promoting tumor stemness as well as tumor intrinsic regulation of T cell trafficking. Both pathways are regulated epigenetically and can be reversed to suppress tumor growth.The first project explores how Th22 cells can promote colon cancer stemness. We found that Th22 cells, through secreting IL-22, mediates cancer stemness through STAT3-mediated regulation of the epigenetic regulator DOT1L. Blocking IL-22 signaling leads to reduced in vivo tumor growth and cancer stemness through DOT1L-mediated gene regulation of stem cell genes. This mechanism predicts survival in colon cancer. The second project is aimed at improving effector T cell trafficking into the tumor. The tumor creates a barrier to T cells by epigenetically repressing production of chemokines (CXCL9 and CXCL10), the key proteins that regulate trafficking of T cells into the tumor. The intrinsic repression in the tumor cells is mediated by the PRC2 complex and can be reversed by pharmacological drug leading to more chemokine production and T cell trafficking. Increased effector T cells and chemokines and decreased PRC2 components predict better survival in colon cancer patients. Finally, a recent project centers on trying to create a more powerful antitumor T cell by epigenetic manipulation. We focused on protein arginine deaminase (PAD)-mediated regulation of T cells. We found that PAD signaling can negatively affect T cells. Using an inhibitor of PAD4, F-Amidine, we observed that PAD inhibition increases T cell survival, proliferation, and effector cytokine expression in activated T cells. Tumor and immune cells influence each other in the tumor microenvironment; some pathways, such as stemness and T cell trafficking, can be epigenetically regulated. Targeting these networks might be a strategy toward treating cancer patients.

[发布机构] University of Michigan

[效力级别] Tumor microenvironment

[关键词] Epigenetics;Tumor microenvironment;Cancer stemness;T cell trafficking;Chemokines;Protein Arginine Deaminase;Genetics;Molecular;Cellular and Developmental Biology;Science;Immunology