Non-canonical PRC1.1 licenses transcriptional response to enable Treg plasticity in immune adaptation

Abstract

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.

Keywords: H2AK119ub1; PRC; Polycomb; Treg; plasticity; tumor-infiltrated Treg.