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

Abstract

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-