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

Daofu Feng, Bo Qin, Krishnendu Pal, Lei Sun, Shamit Dutta, Haidong Dong, Xin Liu, Debabrata Mukhopadhyay, Shengbing Huang, Frank A. Sinicrope

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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.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Jan 1 2019

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Heterografts
Colonic Neoplasms
Apoptosis
Ligands
Drug Therapy
Neoplasms
Cell Death
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinases
DNA Damage
Colorectal Neoplasms
Proteins
Up-Regulation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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BRAF V600E-induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenografts. / Feng, Daofu; Qin, Bo; Pal, Krishnendu; Sun, Lei; Dutta, Shamit; Dong, Haidong; Liu, Xin; Mukhopadhyay, Debabrata; Huang, Shengbing; Sinicrope, Frank A.

In: Oncogene, 01.01.2019.

Research output: Contribution to journalArticle

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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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AU - Feng, Daofu

AU - Qin, Bo

AU - Pal, Krishnendu

AU - Sun, Lei

AU - Dutta, Shamit

AU - Dong, Haidong

AU - Liu, Xin

AU - Mukhopadhyay, Debabrata

AU - Huang, Shengbing

AU - Sinicrope, Frank A.

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