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The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion
Open accessAbstract
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.
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Cites
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Mechanisms Controlling PD-L1 Expression in Cancer
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Regulation of PD-L1 expression in the tumor microenvironment
Yi, M., Niu, M., Xu, L., Luo, S., & Wu, K. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-01027-5 · Cited by 681
Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends
Sun, Q., Hong, Z., Zhang, C., Wang, L., Han, Z., & Ma, D. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01522-4 · Cited by 598
Cancer Epigenetics, Tumor Immunity, and Immunotherapy
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Metadata
- Authors
- Lu, C., Paschall, A. V., Shi, H., Savage, N., Waller, J. L., Sabbatini, M. E., Oberlies, N. H., Pearce, C., & Liu, K.
- Venue
- Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-01
- Volume
- 109
- Issue
- 6
- Pages
- djw283
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2582362986
- Cited by
- 266
- References
- 49
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Lu, C., Paschall, A. V., Shi, H., Savage, N., Waller, J. L., Sabbatini, M. E., Oberlies, N. H., Pearce, C., & Liu, K. (2017). The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion. Journal of the National Cancer Institute. https://doi.org/10.1093/jnci/djw283
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