Author ORCID Identifier
0000-0001-6546-9369
Date of Graduation
5-2017
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Mien-Chie Hung
Committee Member
Liuqing Yang
Committee Member
Jeffrey T. Chang
Committee Member
Zhen Fan
Committee Member
Guang Peng
Abstract
With recent approvals for therapeutic antibodies that block CTLA4, PD-1 and PD-L1, immune checkpoints have emerged as new targets in cancer therapy. In addition, there is accumulating evidence highlighting the role of cancer-associated immunity in patient response to cytotoxic anticancer agents. Inhibitors of poly (ADP-ribose) polymerase (PARP) have shown substantial cytotoxic effects against tumors with defects in DNA damage responses. However, whether a crosstalk between PARP inhibition and immune checkpoints exists remains unclear. Here, it has been shown that PARP inhibitors (PARPis) upregulate PD-L1 expression in multiple cancer cell lines, human xenograft tumors, and syngeneic mouse tumors. Mechanistically, PARPi inactivates GSK3β, which in turn enhances PARPi-mediated PD-L1 upregulation. PARPi attenuates anticancer immunity via upregulation of PD-L1, and blockade of PD-L1 re-sensitizes PARPi-treated cancer cells to T cell killing. The combination of PARPi and anti-PD-L1 therapy compared with each agent alone significantly increased the therapeutic efficacy in vivo. In details, PARPi treatment increases T lymphocytes infiltration in tumors; however, the induced PD-L1 by PARPi on cancer cells inhibits the activation of the infiltrating T lymphocytes. Thus, the addition of PD-L1 blockade to PARPi therapy can re-activate anti-tumor immunity and improve the therapeutic efficacy. This study demonstrates a crosstalk between PARPi and tumor-associated immunosuppression, and provides a rationale for the combination of PARPi and PD-L1 or PD-1 immune checkpoint blockade as a potential therapeutic approach. (Jiao et al., 2017)
Keywords
Cancer Immunotherapy; immune checkpoint; PARP inhibitor; Combination therapy