PT  - JOURNAL ARTICLE
AU  - Xiaosheng Wu
AU  - Yanli Li
AU  - Xin Liu
AU  - Siyu Cao
AU  - Susan M. Harrington
AU  - Chunhua Chen
AU  - Aaron S. Mansfiled
AU  - Roxana S. Dronca
AU  - Sean S. Park
AU  - Yiyi Yan
AU  - Eugene D. Kwon
AU  - Liewei Wang
AU  - Kun Ling
AU  - Haidong Dong
TI  - B7-H1(PD-L1) confers chemoresistance through ERK and p38 MAPK pathway in tumor cells
AID  - 10.1101/308601
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 308601
4099  - http://biorxiv.org/content/early/2018/04/25/308601.short
4100  - http://biorxiv.org/content/early/2018/04/25/308601.full
AB  - Development of resistance to chemotherapy and immunotherapy is a major obstacle in extending the survival of patients with cancer. Although several molecular mechanisms have been identified that can contribute to chemoresistance, the role of immune checkpoint molecules in tumor chemoresistance remains underestimated. It has been recently observed that overexpression of B7-H1(PD-L1) confers chemoresistance in human cancers, however the underlying mechanisms are unclear. Here we show that the development of chemoresistance depends on the increased activation of ERK pathway in tumor cells overexpressing B7-H1. Conversely, B7-H1 deficiency renders tumor cells susceptible to chemotherapy in a cell-context dependent manner through activation of the p38 MAPK pathway. B7-H1 in tumor cells associates with the catalytic subunit of a DNA-dependent serine / threonine protein kinase (DNA-PKcs). DNA-PKcs is required for the activation of ERK or p38 MAPK in tumors expressing B7-H1, but not in B7-H1 negative or B7-H1 deficient tumors. Ligation of B7-H1 by anti-B7-H1 monoclonal antibody (H1A) increased the sensitivity of human triple negative breast tumor cells to cisplatin therapy in vivo. Our results suggest that B7-H1(PD-L1) expression in cancer cells modifies their chemosensitivity towards certain drugs and targeting B7-H1 intracellular signaling pathway is a new way to overcome cancer chemoresistance.