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BRAFV600E-induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenografts

Oncogene volume 38, pages 6752–6766 (2019)Cite this article

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Abstract

Programmed death ligand 1 (PD-L1) is an immune checkpoint protein; however, emerging data suggest that tumor cell PD-L1 may regulate immune-independent and intrinsic cellular functions. We demonstrate regulation of PD-L1 by oncogenic BRAFV600E and investigated its ability to influence apoptotic susceptibility in colorectal cancer (CRC) cells. Endogenous or exogenous mutant vs. wild-type BRAF were shown to increase PD-L1 messenger RNA (mRNA) and protein expression that was attenuated by MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase) inhibition or c-JUN and YAP knockdown. Deletion of PD-L1 reduced tumor cell growth in vitro and in vivo. Loss of PD-L1 was also shown to attenuate DNA damage and apoptosis induced by diverse anti-cancer drugs that could be reversed by restoration of wild-type PD-L1, but not mutants with deletion of its extra- or intracellular domain. The effect of PD-L1 on chemosensitivity was confirmed in MC38 murine tumor xenografts generated from PD-L1-knockout vs. parental cells. Deletion of PD-L1 suppressed BH3-only BIM and BIK proteins that could be restored by re-expression of PD-L1; re-introduction of BIM enhanced apoptosis. PD-L1 expression was significantly increased in BRAFV600E human colon cancers, and patients whose tumors had high vs. low PD-L1 had significantly better survival. In summary, BRAFV600E can transcriptionally upregulate PD-L1 expression that was shown to induce BIM and BIK to enhance chemotherapy-induced apoptosis. These data indicate an intrinsic, non-immune function of PD-L1, and suggest the potential for tumor cell PD-L1 as a predictive biomarker.

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Acknowledgements

This study was supported, in part, by NCI R01 (CA210509-01A1) to F.A.S. D.F. was supported by the Scientific Research Training Program for Young Talents of Tianjin Medical University General Hospital, PRC; current address is Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China. L.S. is supported by the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. The authors’ express their gratitude to Mr. Matthew A. Bockol for downloading TCGA data.

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Authors and Affiliations

  1. Gastrointestinal Research Unit, Rochester, MN, 55905, USA

    Daofu Feng, Bo Qin, Lei Sun, Shengbing Huang & Frank A. Sinicrope

  2. Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, FL, 32224, USA

    Krishnendu Pal, Shamit Dutta & Debabrata Mukhopadhyay

  3. Department of Immunology, Mayo Clinic, Rochester, MN, 55905, USA

    Haidong Dong & Xin Liu

  4. Departments of Medicine and Oncology, Rochester, MN, 55905, USA

    Frank A. Sinicrope

  5. Mayo Clinic and Mayo Comprehensive Cancer Center, Rochester, MN, 55905, USA

    Frank A. Sinicrope

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Feng, D., Qin, B., Pal, K. et al. BRAFV600E-induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenografts. Oncogene 38, 6752–6766 (2019). https://doi.org/10.1038/s41388-019-0919-y

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