| dc.description.abstract | Immunotherapy is one of the fastest growing fields in cancer research and treatment. It largely relies on the immune system and is impacted by tumor infiltrated immune cells, which perform an important function in the tumor environment. Although researchers report great success in cancer treatment, immunotherapy has provided few patients with a favorable prognosis.
To maximize the efficacy of current cancer immunotherapy, researchers must understand how to regulate a different T cell status and how efficacy is affected by other factors. Accumulated studies reported dynamic changes in the epigenetic landscape during T cell development. This suggests that epigenetic regulation is one of the important aspects controlling the process of generating fully functional effector T cells, followed by exhaustion and clearing.
TET family enzymes are important epigenetic regulators closely linked to various cellular processes. Tet2 is a well-known tumor suppressor in various systems, including hematopoietic stem and progenitor cells, T cells, B cells and myeloid cells. However, recent studies reported that Tet2 deficiency in immune cells, including T cells and macrophages, benefit the anti-tumor immunity.
To demonstrate how Tet2 disrupted cytotoxic T cells affect cancer immunotherapy, we established a mouse immunotherapy model and found that a strong delay of melanoma progression in mice transferred with Tet2 deleted CD8+ T cells. Further transcriptome and epigenome analysis revealed that Tet2 deleted tumor infiltrating lymphocytes (TILs) showed augmented activation of immune related pathways. For further validation of the relationship between epigenome remodeling and Tet2-mediated 5hmC generation as well as manipulating Tet2 expression to maximize its beneficial effect on immunotherapy, I developed epigenome profiling technique called sCMS-IP seq and a drug-inducible epigenome editing tool called CiDER, respectively.
In sum, we demonstrated the therapeutic potential of Tet2 inactivation in a specific immune cell type during cancer immunotherapy. It must be noted, however, that Tet2 deficiency is closely associated with various hematology disorders. Therefore, practitioners must balance the tumor promoting and immune-boosting properties of Tet2 during cancer therapy. A temporally controllable system to inactivate Tet2 in specific immune cells might be optimal for pursuing future therapeutic intervention by targeting Tet2. | en |
