Tet2 Promotes Anti-Tumor Immunity By Governing G-Mdscs Andcd8(+)T-Cell Numbers

The host immune response is a fundamental mechanism for attenuating cancer progression. Here we report a role for theDNAdemethylase and tumor suppressorTET2 in host anti-tumor immunity. Deletion of Tet2 in mice elevatesIL-6 levels upon tumor challenge. ElevatedIL-6 stimulates immunosuppressive granulocytic myeloid-derived suppressor cells (G-MDSCs), which in turn reduceCD8(+)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 restoresCD8(+)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 aTET2-mediatedIL-6/G-MDSCs/CD8(+)T-cell immune response cascade that safeguards host adaptive anti-tumor immunity, offering a cell non-autonomous mechanism ofTET2 for tumor suppression.