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.

中文翻译：

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TET2 通过控制 G-MDSC 和 CD8+ T 细胞数量来促进抗肿瘤免疫。

宿主免疫反应是减缓癌症进展的基本机制。在这里，我们报告了 DNA 去甲基化酶和肿瘤抑制因子 TET2 在宿主抗肿瘤免疫中的作用。小鼠中 Tet2 的缺失会在肿瘤攻击时提高 IL-6 水平。升高的 IL-6 会刺激免疫抑制性粒细胞髓源性抑制细胞 (G-MDSC)，从而在肿瘤攻击时减少 CD8 ⁺ T 细胞。因此，在小鼠中系统性敲除 Tet2 会导致同基因肿瘤生长加速，这受到抗 PD-1 阻断的限制。通过抗小鼠 Ly6g 抗体去除 G-MDSC 可恢复Tet2 ^{-/- 中的}CD8 ⁺ T 细胞数量小鼠并重新启动它们的抗肿瘤活性。重要的是，抗 IL-6 抗体治疗可阻断 G-MDSCs 的扩增并抑制同源肿瘤生长。总的来说，这些发现揭示了 TET2 介导的 IL-6/G-MDSCs/CD8 ⁺ T 细胞免疫反应级联，保护宿主适应性抗肿瘤免疫，提供 TET2 的细胞非自主机制来抑制肿瘤。