• Chunwan Lu, Amy V Paschall, Huidong Shi, Natasha Savage, Jennifer L Waller, Maria E Sabbatini, Nicholas H Oberlies, Cedric Pearce, and Kebin Liu.
• Affiliations of authors: Department of Biochemistry and Molecular Biology (CL, AVP, KL), Department of Pathology (NS), and Department of Biostatistics and Epidemiology (JLW), Medical College of Georgia, Augusta, GA; Georgia Cancer Center (CL, AVP, HS, KL) and Department of Biological Sciences (MES), Augusta University, Augusta, GA; Charlie Norwood VA Medical Center, Augusta, GA (CL, AVP, KL); Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC (NHO); Mycosynthetix, Inc., Hillsborough, NC (CP).
• J. Natl. Cancer Inst. 2017 Jan 1; 109 (6).

BackgroundPancreatic 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.MethodsPancreatic 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.ResultsPD-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 tumor growth in a FasL- and CTL-dependent manner.ConclusionsThe Fas-FasL/CTLs and the MLL1-H3K4me3-PD-L1 axis play contrasting roles in pancreatic cancer immune surveillance and evasion. Targeting the MLL1-H3K4me3 axis is an effective approach to enhance the efficacy of checkpoint immunotherapy against pancreatic cancer.© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

61 keywords...

hide…