Mutant APC promotes tumor immune evasion via PD-L1 in colorectal cancer
- 12 August 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (41), 5984-5992
- https://doi.org/10.1038/s41388-021-01972-6
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.Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK047297-20)
This publication has 23 references indexed in Scilit:
- PTEN Loss Increases PD-L1 Protein Expression and Affects the Correlation between PD-L1 Expression and Clinical Parameters in Colorectal CancerPLOS ONE, 2013
- Immortalized Epithelial Cells Derived From Human Colon Biopsies Express Stem Cell Markers and Differentiate In VitroGastroenterology, 2010
- PD-1 and Its Ligands in Tolerance and ImmunityAnnual Review of Immunology, 2008
- Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+T lymphocytes are prognostic factors of human ovarian cancerProceedings of the National Academy of Sciences of the United States of America, 2007
- Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in gliomaNature Medicine, 2006
- B7-H1 glycoprotein blockade: A novel strategy to enhance immunotherapy in patients with renal cell carcinomaUrology, 2005
- Clinical Significance of Programmed Death-1 Ligand-1 and Programmed Death-1 Ligand-2 Expression in Human Esophageal CancerClinical Cancer Research, 2005
- Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasionNature Medicine, 2002
- Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte ActivationThe Journal of Experimental Medicine, 2000
- APC mutations occur early during colorectal tumorigenesisNature, 1992