TET 2 promotes anti‐tumor immunity by governing G‐ MDSC s and CD 8 + T‐cell numbers

Abstract

The host immune response is a fundamental mechanism for attenuating cancer progression. Here we report a role for the DNA demethylase and tumor suppressor TET2 in host anti‐tumor immunity. Deletion of Tet2 in mice elevates IL‐6 levels upon tumor challenge. Elevated IL‐6 stimulates immunosuppressive granulocytic myeloid‐derived suppressor cells (G‐MDSCs), which in turn reduce CD8 + T cells upon tumor challenge. Consequently, systematic knockout of Tet2 in mice leads to accelerated syngeneic tumor growth, which is constrained by anti‐PD‐1 blockade. Removal of G‐MDSCs by the anti‐mouse Ly6g antibodies restores CD8 + T‐cell numbers in Tet2 −/− mice and reboots their anti‐tumor activity. Importantly, anti‐IL‐6 antibody treatment blocks the expansion of G‐MDSCs and inhibits syngeneic tumor growth. Collectively, these findings reveal a TET2‐mediated IL‐6/G‐MDSCs/CD8 + T‐cell immune response cascade that safeguards host adaptive anti‐tumor immunity, offering a cell non‐autonomous mechanism of TET2 for tumor suppression.