Mi-2 promotes immune evasion in melanoma by activating EZH2 methylation

Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitive will provide a significant improvement in patient outcome. Here we identify Mi-2 beta as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Studies in genetically engineered mouse melanoma models indicate that loss of Mi-2 beta rescues the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq analysis shows that Mi-2 beta controls the accessibility of IFN-gamma-stimulated genes (ISGs). Mi-2 beta binds to EZH2 and promotes K510 methylation of EZH2, subsequently activating the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2 beta-targeted inhibitor, Z36-MP5, which reduces Mi-2 beta ATPase activity and reactivates ISG transcription. Consequently, Z36-MP5 induces a response to immune checkpoint inhibitors in otherwise resistant melanoma models. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones. Mi-2 beta is an enzyme of the chromodomain helicase DNA family with roles in chromatin assembly, genomic stability and gene repression. Here the authors report that Mi-2 beta promotes immune evasion by activating EZH2 methylation and that loss of Mi-2 beta or its inhibition promote anti-tumor immune responses in preclinical melanoma models.