Parp Inhibitor Upregulates Pd-L1 Expression and Enhances Cancer-Associated Immunosuppression

<p>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)</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2017

Authors dc:creator

• Jiao, Shiping
• <p>0000-0001-6546-9369</p>

Contributors dc:contributor

• Mien-Chie Hung
• Liuqing Yang
• Jeffrey T. Chang

• Cancer Immunotherapy; immune checkpoint; PARP inhibitor; Combination therapy
• Cancer Biology
• Medical Immunology
• Neoplasms
• Oncology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/739

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1784