| First Author | Long X | Year | 2024 |
| Journal | Nat Immunol | Volume | 25 |
| Issue | 3 | Pages | 525-536 |
| PubMed ID | 38356061 | Mgi Jnum | J:392162 |
| Mgi Id | MGI:8408048 | Doi | 10.1038/s41590-024-01746-8 |
| Citation | Long X, et al. (2024) Targeting JMJD1C to selectively disrupt tumor T(reg) cell fitness enhances antitumor immunity. Nat Immunol 25(3):525-536 |
| abstractText | 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. |
