Targeting JMJD1C to selectively disrupt tumor Treg cell fitness enhances antitumor immunity

Nat Immunol. 2024 Feb 14. doi: 10.1038/s41590-024-01746-8.

Xuehui Long ^# ¹, Sulin Zhang ^# ², Yuliang Wang ^# ¹, Jingjing Chen ^# ¹, Yanlai Lu ^# ¹, Hui Hou ^# ², Bichun Lin ^# ¹, Xutong Li ², Chang Shen ², Ruirui Yang ², Huamin Zhu ¹, Rongrong Cui ², Duanhua Cao ², Geng Chen ², Dan Wang ², Yun Chen ¹, Sulan Zhai ¹, Zhiqin Zeng ¹, Shusheng Wu ¹, Mengting Lou ¹, Junhong Chen ¹, Jian Zou ³, Mingyue Zheng ⁴, Jun Qin ⁵, Xiaoming Wang ⁶

Affiliations

1 Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
2 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
3 Department of Laboratory Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
4 Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. [email protected].
5 CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
6 Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Nanjing, China. [email protected].
# Contributed equally.

PMID: 38356061 DOI: 10.1038/s41590-024-01746-8

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-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.

Products

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Description

Target

Research Area
HY-162275

JMJD1C-IN-1

JMJD1C Inhibitor

Others

Cancer

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