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Immunohistochemical Staining of B7-H1 PD-L1 on Paraffin-embedded Slides of Pancreatic Adenocarcinoma Tissue
Published on: January 3, 2013
The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion
Chunwan Lu1, Amy V Paschall1, Huidong Shi1
1Affiliations 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).
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.
Insights
Pancreatic cancer resists immunotherapy due to high PD-L1 expression. Targeting MLL1 enhances anti-PD-1/PD-L1 therapy by reducing PD-L1, boosting immune response against tumors.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Pancreatic cancer exhibits resistance to anti-PD-1/PD-L1 immunotherapy.
- The mechanisms driving pancreatic cancer's resistance to checkpoint immunotherapy remain unclear.
- Understanding PD-L1 regulation is crucial for overcoming immune evasion in pancreatic cancer.
Purpose of the Study:
- To elucidate the regulatory mechanisms of PD-L1 expression in pancreatic cancer.
- To investigate the role of PD-L1 in pancreatic cancer immune evasion.
- To identify potential therapeutic targets for enhancing immunotherapy efficacy.
Main Methods:
- Utilized pancreatic cancer mouse models and human specimens to assess PD-L1 and PD-1 expression.
- Employed histone methyltransferase inhibitors, RNA interference (RNAi), and gene overexpression studies.
- Analyzed the molecular mechanisms regulating PD-L1 expression.
Main Results:
- PD-L1 expression was detected in 60-90% of human pancreatic carcinomas and 90% of cell lines.
- PD-1 was expressed on 51.2-52.1% of tumor-infiltrating cytotoxic T lymphocytes (CTLs).
- MLL1 (histone methyltransferase) directly binds to the cd274 promoter, catalyzing H3K4me3 to activate PD-L1 transcription, which was reversed by MLL1 inhibition, suppressing tumor growth in combination with immunotherapy.
Conclusions:
- The MLL1-H3K4me3-PD-L1 axis is a key regulator of pancreatic cancer immune evasion.
- Targeting the MLL1-H3K4me3 axis enhances checkpoint immunotherapy efficacy against pancreatic cancer.
- The Fas-FasL/CTLs pathway plays a contrasting role in pancreatic cancer immune surveillance and evasion.
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