Cancer stem cells (CSCs) drive tumor initiation, progression, metastasis, and drug resistance. We report here that programmed cell death ligand 1 (PD-L1) is constitutively expressed in cancer cells to maintain and expand CSC through a novel mechanism in addition to promoting cancer cell immune evasion. We discovered that PD-L1 interacts with receptor Frizzled 6 to activate β-catenin signaling and increase β-catenin-targeted gene expression, such as a putative stem cell marker leucine-rich-repeat-containing G-protein-coupled receptor 5. Blockage of PD-L1 function, using a specific small hairpin RNA or a specific antibody, inhibits disease progression by reducing the CSC population in both colorectal and breast tumors. Moreover, β-catenin conversely regulates PD-L1 expression through a β-catenin complex binding site in the PD-L1 promoter. Our discoveries reveal that besides assistant tumor cell immune escaping, PD-L1 and β-catenin signaling form a positive feedback loop to promote cancer progression through CSC maintenance and expansion.
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We thank Dr Suwon Kim for her assistance with the Gene Expression Omnibus. We also thank Kiera Fleck, Alan Ross, and Jax Ramsey for their help with the manuscript.
This work was supported by grants National Institutes of Health/National Cancer Institute (CA249517 to WK); Arizona State University (Startup fund 5300 to WK); National Institutes of Health National/Institute of Dental and Craniofacial (DE024607 to YS and WK).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Fu, L., Fan, J., Maity, S. et al. PD-L1 interacts with Frizzled 6 to activate β-catenin and form a positive feedback loop to promote cancer stem cell expansion. Oncogene 41, 1100–1113 (2022). https://doi.org/10.1038/s41388-021-02144-2