MLL3 enhances the transcription of PD-L1 and regulates anti-tumor immunity.

Tumor cells utilize the overexpression of the programmed death-1 ligand 1(PD-L1) to escape T-cell controlled immune-surveillance. The clinical therapy that dilapidates PD1 or PD-L1-mediated cancer tolerance has pushed out the need to uncover the molecular regulation of PD-L1 overexpression in the tumor cell. In this study, we identify histone methyltransferase mixed-lineage leukemia protein 3 (MLL3) as a critical regulator of PD-L1 in prostate cancer cells. MLL3 and PD-L1 were highly expressed in the metastatic cancer tissues, compared to the primary cancer tissues. Furthermore, their expressions were highly correlated in the cancer tissues in the databases of TCGA and Xiangya Hospital. We found that MLL3 bound to the enhancer of PD-L1. Depletion of MLL3 decreased the binding level of H3K4me1 in the enhancer of PD-L1 and Pol II Ser-5p in the promoter of PD-L1. Importantly, MLL3 depletion impaired the mouse xenograft growth and decreased the response to PD-L1 antibody treatment in mice. The findings extend the understanding of the biology regulation of PD-L1 transcription and identify the histone writer MLL3 in an important immune checkpoint, and give prominence to a hidden therapeutic target to conquer immune evasion by tumor cells.