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Targeting JMJD1C to selectively disrupt tumor T reg cell fitness enhances antitumor immunity.

Xuehui LongSulin ZhangYuliang WangJingjing ChenYanlai LuHui HouBichun LinXutong LiChang ShenRuirui YangHuamin ZhuRongrong CuiDuanhua CaoGeng ChenDan WangYun ChenSulan ZhaiZhiqin ZengShusheng WuMengting LouJunhong ChenJian ZouMingyue ZhengJun QinXiaoming Wang
Published in: Nature immunology (2024)
Regulatory T (T reg ) cells are critical for immune tolerance but also form a barrier to antitumor immunity. As therapeutic strategies involving T reg cell depletion are limited by concurrent autoimmune disorders, identification of intratumoral T reg cell-specific regulatory mechanisms is needed for selective targeting. Epigenetic modulators can be targeted with small compounds, but intratumoral T reg cell-specific epigenetic regulators have been unexplored. Here, we show that JMJD1C, a histone demethylase upregulated by cytokines in the tumor microenvironment, is essential for tumor T reg cell fitness but dispensable for systemic immune homeostasis. JMJD1C deletion enhanced AKT signals in a manner dependent on histone H3 lysine 9 dimethylation (H3K9me2) demethylase and STAT3 signals independently of H3K9me2 demethylase, leading to robust interferon-γ production and tumor T reg cell fragility. We have also developed an oral JMJD1C inhibitor that suppresses tumor growth by targeting intratumoral T reg cells. Overall, this study identifies JMJD1C as an epigenetic hub that can integrate signals to establish tumor T reg cell fitness, and we present a specific JMJD1C inhibitor that can target tumor T reg cells without affecting systemic immune homeostasis.
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