title: The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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).
authors.forename: Chunwan
authors.initials: C
authors.lastname: Lu
authors.affiliation: 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).
authors.forename: Amy V
authors.initials: AV
authors.lastname: Paschall
authors.affiliation: 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).
authors.forename: Huidong
authors.initials: H
authors.lastname: Shi
authors.affiliation: 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).
authors.forename: Natasha
authors.initials: N
authors.lastname: Savage
authors.affiliation: 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).
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Waller
authors.affiliation: 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).
authors.forename: Maria E
authors.initials: ME
authors.lastname: Sabbatini
authors.affiliation: 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).
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Oberlies
authors.affiliation: 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).
authors.forename: Cedric
authors.initials: C
authors.lastname: Pearce
authors.affiliation: 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).
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000032:analysis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D002277:Carcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000628:therapy*; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D044127:Epigenesis, Genetic; D053222:Fas Ligand Protein / Q000235:genetics; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000628:therapy*; D010879:Piperazines / Q000494:pharmacology; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry; D019139:Tumor Escape; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D053222:Fas Ligand Protein; D007211:Indoles; C497422:KMT2A protein, human; D010879:Piperazines; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; C009654:verticillins; D051788:Myeloid-Lymphoid Leukemia Protein; C002511:chaetocin; D011495:Histone-Lysine N-Methyltransferase