Poly (ADP-ribose) polymerase (PARP)-inhibitors are an emerging class of medicines for women with recurrent ovarian cancer and improving patients’ prognosis. PARP-inhibitors became the first effective and tolerable maintenance treatment after surgery and chemotherapy to prevent a recurrence. The main mechanisms of action for the treatment benefit is based on targeting cancer cells and inducing cancer cell death. It has been studies that cancer develops the strategies to escape from the host immune system and grow invasively. The idea to boost immune activity against cancer has become a very promising treatment approach in the combination of chemotherapies.
Through many clinical trials and basic research, the evidence that PARP-inhibitors can enhance cancer-immunity is accumulating. Recently, pairing PARP-inhibitors with immunostimulatory drugs which can boost the anti-cancer immune system’s ability to fight cancer is a very attractive idea. Although several clinical trials are going on now, how PARP inhibitors directly impact on host immune system is not clear yet. In this proposal, we aim to examine the effects of PARP-inhibitor on immune cells, especially their anti-cancer T-lymphocytes. T-lymphocytes are circulating the whole body to surveillance and once they come across targets, such as invading pathogens or cancerous cells, they start to proliferate and differentiate into professional killing cells. The process requires high cellular energy and causes a lot of stress in T-lymphocytes. We will address how PARP-inhibitors impact such a process to develop an anti-cancer activity. Our hypothesis is PARP-inhibitors support the energy metabolism in T-lymphocytes for the successful development of effector T cell subset. We will examine how the proliferation and differentiation of T-lymphocytes can be changed by PARP-inhibitors by analyzing the number of cell divisions, anti-tumor activity and metabolic markers in T-lymphocytes. The cancer control efficacy will be tested by measuring the cancer growth and survival of ovarian cancer mice models.
The results from our research will add new knowledge to optimize the current clinical treatment protocol of PARP-inhibitors for the combination with immunomodulatory agents. Our long-term goal is to find the effective combination treatment with PARP-inhibitors for long-lasting anti-cancer immune activity in patients with ovarian cancer and potentially other types of cancers.