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

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, surprisingly licensing aTreg transcriptional programs beyond its repressive role. Disruption of PRC1.1 via Kdm2b ablation or pharmacological inhibition with iBP, a novel 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.