The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion

J Natl Cancer Inst. 2017 Jan 28;109(6):djw283. doi: 10.1093/jnci/djw283. Print 2017 Jan.


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 tumor 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 surveillance and evasion. Targeting the MLL1-H3K4me3 axis is an effective approach to enhance the efficacy of checkpoint immunotherapy against pancreatic cancer.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Antibodies, Monoclonal / therapeutic use*
  • B7-H1 Antigen / analysis
  • B7-H1 Antigen / genetics*
  • B7-H1 Antigen / immunology
  • B7-H1 Antigen / metabolism*
  • Carcinoma / genetics
  • Carcinoma / immunology
  • Carcinoma / metabolism*
  • Carcinoma / therapy*
  • Cell Line, Tumor
  • DNA Methylation / drug effects
  • Down-Regulation / drug effects
  • Epigenesis, Genetic
  • Fas Ligand Protein / genetics
  • Female
  • Histone-Lysine N-Methyltransferase / analysis
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Humans
  • Immunotherapy
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Myeloid-Lymphoid Leukemia Protein / analysis
  • Myeloid-Lymphoid Leukemia Protein / antagonists & inhibitors
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Neoplasm Transplantation
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / therapy*
  • Piperazines / pharmacology
  • Programmed Cell Death 1 Receptor / analysis
  • Programmed Cell Death 1 Receptor / metabolism*
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • T-Lymphocytes, Cytotoxic / chemistry
  • Tumor Escape
  • Tumor Microenvironment / immunology


  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • Fas Ligand Protein
  • Indoles
  • KMT2A protein, human
  • Piperazines
  • Programmed Cell Death 1 Receptor
  • RNA, Messenger
  • verticillins
  • Myeloid-Lymphoid Leukemia Protein
  • chaetocin
  • Histone-Lysine N-Methyltransferase