The MLL1-H3K4me3 axis-mediated PD-L1 expression and pancreatic cancer immune evasion

Background: Pancreatic cancer is one of the cancers where anti-PD-L1/PD-1 immunotherapy has been unsuccessful. What confers pancreatic cancer resistance to checkpoint immunotherapy is unknown. The aim of this study is to elucidate the underlying mechanism of PD-L1 expression regulation in the context of pancreatic cancer immune evasion. Methods: Pancreatic cancer mouse models and human specimens were used to determine PD-L1 and PD-1 expression and cancer immune evasion. Histone methyltransferase inhibitors, RNAi, and overexpression were used to elucidate the underlying molecular mechanism of PD-L1 expression regulation. All statistical tests were two-sided. Results: PD-L1 is expressed in 60% to 90% of tumor cells in human pancreatic carcinomas and in nine of 10 human pancreatic cancer cell lines. PD-1 is expressed in 51.2% to 52.1% of pancreatic tumor-infiltrating cytotoxic T lymphocytes (CTLs). Tumors grow statistically significantly faster in FasL-deficient mice than in wild-type mice (P = .03-.001) and when CTLs are neutralized (P = .03-<.001). H3K4 trimethylation (H3K4me3) is enriched in the cd274 promoter in pancreatic tumor cells. MLL1 directly binds to the cd274 promoter to catalyze H3K4me3 to activate PD-L1 transcription in tumor cells. Inhibition or silencing of MLL1 decreases the H3K4me3 level in the cd274 promoter and PD-L1 expression in tumor cells. Accordingly, Inhibition of MLL1 in Combination with anti-PD-L1 or anti-PD-1 Antibody Immunotherapy Effectively Suppresses Pancreatic Tum. Growth in A FasL- and CTL-dependent Manner. Conclusions: the Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 Axis Play Contrasting Roles in Pancreatic Cancer Immune Survlnc. and Evasion. Targeting the MLL1-H3K4me3 Axis is An Effective Approach to Enhance the Efficacy of Checkpoint Immunotherapy Against Pancreatic Cancer.