ArticleJournal of the National Cancer Institute2017
The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion.
Article in Journal of the National Cancer Institute, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 168 papers, 1 of them a synthesis that pooled it.
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Who cites it
168 citing papers in PubMed, 1 synthesis or guideline pooled it, 284 citations in OpenAlex.
- PD-1/PD-L1 immune checkpoint blockade in breast cancer: research insights and sensitization strategies.Molecular cancer · 2024Pooled it
- MLL1 downregulation drives hair cell ferroptosis via mitochondrial and endoplasmic reticulum stress mechanisms through PERK-eIF2α-ATF4-Chop and PI3K/Akt-Lrp1 signaling pathway.Chinese medical journal · 2026Article
- Genomic analysis of oesophageal carcinoma (EC) identifies recurrent mutations in histone methyltransferases as a distinctive subset.Oncogene · 2026Article
- Regulation of immune checkpoint molecules in cancer immune evasion and therapy.Nature reviews. Cancer · 2026Review
- UDP-glucuronate decarboxylase 1 promotes tumor immune evasion by accelerating KMT2D loss in hepatocellular carcinoma.Journal for immunotherapy of cancer · 2026Article
- Aging and cancer: current understandings and future perspectives.Signal transduction and targeted therapy · 2026Review
- KMT2D depletion promotes KRAS-induced pancreatic carcinogenesis independent of TP53.The Journal of biological chemistry · 2026Article
- Histone modifications across cancers: mechanisms, therapy and clinical translation.Molecular cancer · 2026Review
- Strategies to target PD-1/PD-L1 in the tumor microenvironment.Cellular oncology (Dordrecht, Netherlands) · 2026Review
- Epigenetic modulation to overcome immune suppression in pancreatic cancer.Clinical epigenetics · 2026Review
- Research progress on the correlation between OPN and immune escape of gastric cancer.Clinical and experimental medicine · 2026Review
- Intracellular PD-L1: Functions, Regulation, and Therapeutic Implications.International journal of biological sciences · 2026Review
- Biomarker-driven neoadjuvant immunotherapy in triple-negative breast cancer: emerging therapeutic targets FOXP3 and WT1.Frontiers in immunology · 2026Review
- Total Synthesis and Anticancer Study of (+)-Verticillin A.Journal of the American Chemical Society · 2025Article
- Slc7a5 promotes T cell anti-tumor immunity through sustaining cytotoxic T lymphocyte effector function.Oncogene · 2025Article
- Activation of PD-1/PD-L1 immune checkpoint by Zika virus.PLoS pathogens · 2025Article
- Studies on the epipolythiodioxopiperazine alkaloid verticillin D: Scaled production, streamlined purification, and absolute configuration.Phytochemistry · 2025Article
- Recent Advances in Nanotechnology-Based Approaches for Ferroptosis Therapy and Imaging Diagnosis in Pancreatic Cancer.Pharmaceutics · 2025Review
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108 more citing papers are in PubMed but not listed here.
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9 authors at 4 institutions in 1 country.
Funding
Abstract
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.
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