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

5 Scopus citations

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

Keywords

  • Cancer research
  • Oncology

ASJC Scopus subject areas

  • General

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    Wu, X., Li, Y., Liu, X., Chen, C., Harrington, S. M., Cao, S., Xie, T., Orzechowski, A., Pham, T., Mansfield, A., Yan, Y., Kwon, E. D., Wang, L. M., Ling, K., & 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