Li Ting, Zhao Yingying, Li Qian, Sun Zhaoran, Wang Ni, Xing Liangyu, Tang Nan, Mao Runyuan, Wang Yuxin, Su Jiacheng, Huo Dawei, Dong Feng, Zhao Xiujuan, Cao Lei, Kong Yu, Gong Meihan, Liu Ziyi, Li Wei, Lv Xuejiao, Ning Hanhan, Hu Deqing, Zhou Yan, Li Bin, Feng Xiaoming, Helin Kristian, Chen Fei Xavier, Wu Xudong
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Cancer, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University Cancer Institute and Hospital, Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Medical Epigenetics, Shanghai Key Laboratory of Radiation Oncology, Human Phenome Institute, Fudan University, Shanghai, China.
Mol Cell. 2025 Jul 3;85(13):2517-2534.e6. doi: 10.1016/j.molcel.2025.05.029. Epub 2025 Jun 16.
Polycomb repressive complexes (PRCs) sustain regulatory T (Treg) cell identity through transcriptional silencing, yet their role in modulating Treg functional plasticity during immune adaptation remains unclear. Here, we identify KDM2B, a defining component of non-canonical PRC1.1, as a critical regulator for sustaining the proportion and immunosuppressive functions of active Treg (aTreg) cells without altering Treg abundance or identity. Mechanistically, PRC1.1 deposits H2AK119 monoubiquitylation (H2AK119ub1) at active promoters, enabling rather than repressing transcriptional activation of aTreg programs. Disruption of PRC1.1 via Kdm2b ablation or pharmacological inhibition with iBP, a selective inhibitor, reduces H2AK119ub1, blunts stimulus-dependent transcriptional activation, and suppresses Treg activation. Notably, Treg-specific Kdm2b deletion in melanoma-bearing mice enhances anti-tumor immunity and synergizes with anti-PD-L1 therapy. Therefore, our study underscores H2AK119ub1 as a dual-function epigenetic mark and PRC1.1 as a molecular rheostat fine-tuning Treg adaptability, establishing PRC1.1 as a therapeutic target to decouple immune suppression in cancer while preserving Treg homeostasis.
多梳抑制复合物（PRCs）通过转录沉默维持调节性T（Treg）细胞的特性，但其在免疫适应过程中调节Treg功能可塑性的作用仍不清楚。在此，我们鉴定出非经典PRC1.1的一个关键成分KDM2B，它是维持活性Treg（aTreg）细胞比例和免疫抑制功能的关键调节因子，而不会改变Treg的丰度或特性。从机制上讲，PRC1.1在活性启动子处沉积H2AK119单泛素化（H2AK119ub1），促进而非抑制aTreg程序的转录激活。通过Kdm2b基因敲除或用选择性抑制剂iBP进行药理抑制来破坏PRC1.1，会减少H2AK119ub1，减弱刺激依赖性转录激活，并抑制Treg激活。值得注意的是，在荷黑素瘤小鼠中特异性敲除Treg中的Kdm2b可增强抗肿瘤免疫力，并与抗PD-L1疗法协同作用。因此，我们的研究强调H2AK119ub1是一种具有双重功能的表观遗传标记，而PRC1.1是微调Treg适应性的分子变阻器，确立了PRC1.1作为在保留Treg稳态的同时解除癌症免疫抑制的治疗靶点。
