Targeting B7-H1 (PD-L1) sensitizes cancer cells to chemotherapy

Xiaosheng Wu, Yanli Li, Xin Liu, Chunhua Chen, Susan M. Harrington, Siyu Cao, Tiancheng Xie, Amanda Orzechowski, Tu Pham, Aaron Mansfield, Yiyi Yan, Eugene D Kwon, Liewei M Wang, Kun Ling, Haidong M Dong

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Development of resistance to chemotherapy is a major obstacle in extending the survival of patients with cancer. Although originally defined as an immune checkpoint molecule, B7-H1 (also named as PD-L1 or CD274) was found to play a role in cancer chemoresistance; however, the underlying mechanism of action of B7-H1 in regulation of chemotherapy sensitivity remains unclear in cancer cells. Here we show that development of chemoresistance depends on an increased activation of ERK in cancer cells overexpressing B7-H1. Conversely, B7-H1 knockout (KO) by CRISPR/Cas9 renders human cancer cells susceptible to chemotherapy in a cell-context dependent manner through a reduced activation of p38 MAPK. B7-H1 was found to associate with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and this association promoted or maintained the activation of ERK or p38 MAPK in cancer cells. Importantly, we found that targeting B7-H1 by anti-B7-H1 monoclonal antibody (H1A) increased the sensitivity of human triple negative breast cancer cells to cisplatin therapy in vivo. Our results suggest that targeting B7-H1 by an antibody capable of disrupting B7-H1 signals may be a new approach to sensitize cancer cells to chemotherapy.

Original languageEnglish (US)
Article numbere01039
JournalHeliyon
Volume4
Issue number12
DOIs
StatePublished - Dec 1 2018

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Drug Therapy
Neoplasms
p38 Mitogen-Activated Protein Kinases
Clustered Regularly Interspaced Short Palindromic Repeats
B7 Antigens
DNA-Activated Protein Kinase
Catalytic DNA
Triple Negative Breast Neoplasms
Cisplatin
Catalytic Domain
Monoclonal Antibodies
Survival
Antibodies
DNA
Therapeutics

Keywords

  • Cancer research
  • Oncology

ASJC Scopus subject areas

  • General

Cite this

Wu, X., Li, Y., Liu, X., Chen, C., Harrington, S. M., Cao, S., ... Dong, H. M. (2018). Targeting B7-H1 (PD-L1) sensitizes cancer cells to chemotherapy. Heliyon, 4(12), [e01039]. https://doi.org/10.1016/j.heliyon.2018.e01039

Targeting B7-H1 (PD-L1) sensitizes cancer cells to chemotherapy. / Wu, Xiaosheng; Li, Yanli; Liu, Xin; Chen, Chunhua; Harrington, Susan M.; Cao, Siyu; Xie, Tiancheng; Orzechowski, Amanda; Pham, Tu; Mansfield, Aaron; Yan, Yiyi; Kwon, Eugene D; Wang, Liewei M; Ling, Kun; Dong, Haidong M.

In: Heliyon, Vol. 4, No. 12, e01039, 01.12.2018.

Research output: Contribution to journalArticle

Wu, X, Li, Y, Liu, X, Chen, C, Harrington, SM, Cao, S, Xie, T, Orzechowski, A, Pham, T, Mansfield, A, Yan, Y, Kwon, ED, Wang, LM, Ling, K & Dong, HM 2018, 'Targeting B7-H1 (PD-L1) sensitizes cancer cells to chemotherapy', Heliyon, vol. 4, no. 12, e01039. https://doi.org/10.1016/j.heliyon.2018.e01039
Wu X, Li Y, Liu X, Chen C, Harrington SM, Cao S et al. Targeting B7-H1 (PD-L1) sensitizes cancer cells to chemotherapy. Heliyon. 2018 Dec 1;4(12). e01039. https://doi.org/10.1016/j.heliyon.2018.e01039
Wu, Xiaosheng ; Li, Yanli ; Liu, Xin ; Chen, Chunhua ; Harrington, Susan M. ; Cao, Siyu ; Xie, Tiancheng ; Orzechowski, Amanda ; Pham, Tu ; Mansfield, Aaron ; Yan, Yiyi ; Kwon, Eugene D ; Wang, Liewei M ; Ling, Kun ; Dong, Haidong M. / Targeting B7-H1 (PD-L1) sensitizes cancer cells to chemotherapy. In: Heliyon. 2018 ; Vol. 4, No. 12.
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