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

Research output: Contribution to journalArticle

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

Feng, Daofu ; Qin, Bo ; Pal, Krishnendu ; Sun, Lei ; Dutta, Shamit ; Dong, Haidong ; Liu, Xin ; Mukhopadhyay, Debabrata ; Huang, Shengbing ; Sinicrope, Frank A. / BRAF V600E-induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenografts. In: Oncogene. 2019.
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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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