Abstract
PD-L1 expression is elevated in various human cancers, including colorectal cancer. High levels of PD-L1 expressed on tumor epithelial cells are one of the potential mechanisms by which tumor cells become resistant to immune attack. However, PD-L1 regulation in tumor cells is not fully understood. Here we demonstrate that mutations in the adenomatous polyposis coli (APC) gene lead to colonic epithelial cell resistance to CD8+ T cell cytotoxicity by induction of PD-L1 expression. Mechanistically, this occurs as a result of the β-catenin/TCF4 complex binding to the PD-L1 promoter, leading to increased transcription. Our findings not only reveal a novel mechanism by which APC mutations induce tumor immune evasion via an immune checkpoint pathway but also pave the way for developing β-catenin or TCF4 inhibitors as possible new options for immune checkpoint inhibition.
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Acknowledgements
We thank the National Colorectal Cancer Research Alliance (NCCRA) for its generous support (to R.N.D.).
Funding
This work was supported in part by Flow Cytometry & Cell Sorting Unit, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313).
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D.W. designed and supervised the study. B.C., J.W., and Y.X. performed the experiments. J.W.S. provided the cells. D.W. wrote the manuscript. D.W. and R.N.D. reviewed and edited the manuscript. R.N.D. provided the funding.
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Cen, B., Wei, J., Wang, D. et al. Mutant APC promotes tumor immune evasion via PD-L1 in colorectal cancer. Oncogene 40, 5984–5992 (2021). https://doi.org/10.1038/s41388-021-01972-6
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DOI: https://doi.org/10.1038/s41388-021-01972-6
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