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PD-L1 interacts with Frizzled 6 to activate β-catenin and form a positive feedback loop to promote cancer stem cell expansion

Oncogene volume 41, pages 1100–1113 (2022)Cite this article

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Abstract

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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Fig. 1: Tumor-expressed PD-L1 contributes to cancer cell growth and metastasis in human colorectal cancer (CRC) HCT 116 and breast cancer MDA-MB-231 cell lines.
Fig. 2: PD-L1 positively regulates β-catenin signaling activity in CRC and breast cancer in vitro and in vivo.
Fig. 3: PD-L1 expression contributes to CSC expansion and LgR5 expression.
Fig. 4: PD-L1 expression in the transgenic Apcflox/flox/CDX2-CRE colorectal tumor mouse also contributes to stem cell expansion.
Fig. 5: PD-L1 expression is co-related with the expressions of LgR5 and other stem cell markers in breast and gastric cancer patient samples.
Fig. 6: β-Catenin transcriptionally regulates PD-L1 expression in HCT 116 and MDA-MB-231 cancer cell lines.
Fig. 7: PD-L1 interacts with FDZ6 to activate β-catenin signaling in HCT 116 and MDA-MB-231 cancer cells.
Fig. 8: Graphical summary.

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Acknowledgements

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.

Funding

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).

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Authors and Affiliations

  1. Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Arizona State University, Tempe, AZ, USA

    Lingchen Fu, Grant McFadden, Yixin Shi & Wei Kong

  2. Center for Cellular and Molecular Diagnostics, Tulane University School of Medicine, New Orleans, LA, USA

    Jia Fan & Sudipa Maity

  3. Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, USA

    Jia Fan & Sudipa Maity

  4. School of Life Sciences, Arizona State University, Tempe, AZ, USA

    Grant McFadden & Yixin Shi

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  1. Lingchen Fu
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Contributions

LF and WK conceptualized the study and designed the experiments. LF, WK, and JF performed the experiments. LF, WK, YS, GM, and JF wrote the manuscript. SM assisted with LC-MS/MS data analysis. All authors discussed results and participated in manuscript preparation and editing. WK, YS, and GM supervised the study.

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Correspondence to Yixin Shi or Wei Kong.

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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

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