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Mutant APC promotes tumor immune evasion via PD-L1 in colorectal cancer

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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Fig. 1: Alteration of APC affects PD-L1 expression via a β-catenin/TCF4 pathway.
Fig. 2: Knockout or overexpression of APC alters PD-L1 expression via a β-catenin/TCF4 pathway.
Fig. 3: Loss of APC induces PD-L1 transcription by binding of β-catenin/TCF4 complex to PD-L1 promoter.
Fig. 4: Loss of APC induces cell resistance to CD8+ T cell cytotoxicity by induction of PD-L1 via the β-catenin/TCF4 pathway.
Fig. 5: Deletion of Apc induces tumor immune evasion by induction of PD-L1 in vivo.

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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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Correspondence to Raymond N. DuBois.

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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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