BRAF V600E -induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenografts

• Published in: Oncogene 2019-10, Vol.38 (41), p.6752-6766
• Main Authors: Feng, Daofu, Qin, Bo, Pal, Krishnendu, Sun, Lei, Dutta, Shamit, Dong, Haidong, Liu, Xin, Mukhopadhyay, Debabrata, Huang, Shengbing, Sinicrope, Frank A
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; BIM protein; c-Jun protein; Cancer; Cell Line, Tumor; Chemotherapy; Clonal deletion; Colon cancer; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; DNA damage; Extracellular signal-regulated kinase; Gene expression; Gene Knockdown Techniques; Humans; Immune checkpoint; Immune response; Immunosuppressive agents; Kinases; MAP kinase; Mice; PD-L1 protein; Protein kinase; Proteins; Proto-Oncogene Proteins B-raf - metabolism; Transcription factors; Tumors; Up-Regulation; Xenograft Model Antitumor Assays; Xenografts; Yes-associated protein
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-019-0919-y

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 BRAF 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 BRAF human colon cancers, and patients whose tumors had high vs. low PD-L1 had significantly better survival. In summary, BRAF 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.