Pim2 negatively regulates anti-tumor immunity of CD8 T cells through modulating Ezh2 4416

Abstract Description The Pim kinase family is critically involved in tumorigenesis, yet its role in primary T cells is not well studied. We previously reported that Pim2 negatively regulates T-cell responses to alloantigen. To further study how Pim2 impacts anti-tumor immunity of CD8 T cells, we generated Pim2-/- Pmel mice and performed adoptive cell therapy (ACT). We found that Pim2 constrains effector differentiation and persistence of CD8 T cells and therefore Pim2-/- CD8 T cells were more potent than WT cells to control melanoma growth. Mechanistically, Pim2 phosphorylates and inhibits downstream target Vprbp, a kinase to phosphorylate and stabilize Ezh2. Consistent with this, Pim2 deficiency increased Ezh2 expression and H3K27 methylation in CD8 T cells. Increased Ezh2 activity in Pim2-/- CD8 T cells inhibited autophagy and therefore enhanced glycolytic metabolism for driving effector T-cell differentiation in the tumor. On the other hand, increased Ezh2 activity contributed to elevated progenitor-like/memory differentiation within Pim2-/- CD8 T cells in the lymphoid organs. In human T cells, silence Pim2 also increased cytokine production and effector differentiation. A Pim2-specific inhibitor improved murine T-cell immunity against melanoma and increased activity of human melanoma-specific T cells and CD19 CAR-T cells. Taken together, Pim2 is a promising target for improving cancer immunotherapy through enhancing effector differentiation and persistence of T cells. Funding Sources R01 CA258440 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)