Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity
Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity | |
Author | Long, XH; Zhang, SL; Wang, YL; Chen, JJ; Lu, YL; Hou, H; Lin, BC; Li, XT; Shen, C; Yang, RR; Zhu, HM; Cui, RR; Cao, DH; Chen, G; Wang, D; Chen, Y; Zhai, SL; Zeng, ZQ; Wu, SS; Lou, MT; Chen, JH; Zou, J; Zheng, MY; Qin, J; Wang, XM |
Journal | NATURE IMMUNOLOGY |
Pub Year | 2024 |
Type | |
Abstract | 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-gamma 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. |
Issue | 25 |
Volume | 25 |
SCI | 27.7 |