PARP inhibitor-induced anti-tumour chemokine response is suppressed by dipeptidyl peptidase 4 (DPP4) in ovarian cancer.

BACKGROUND: Inhibitors of poly(ADP-ribose) polymerase (PARPi, e.g. olaparib) induce a tumour-suppressive chemokine release via STING in homologous recombination deficient (HRD) and proficient (HRP) cancers. METHODS: Dose-dependent effects of olaparib on HRD (ID8-Brca2((-/-))) and HRP (ID8) ovarian cancer cell proliferation and chemokine release. Survival of immunocompetent and immunocompromised ID8 mouse models treated with different olaparib doses. Inhibition and overexpression of the chemokine-inactivating dipeptidyl peptidase 4 (mDPP4) in HRD and HRP mouse models. Correlation of hDPP4 immunohistochemistry staining with survival in 208 high-grade serous ovarian cancer patients. RESULTS: In our study, olaparib induced the chemokines mCCL5 and mCXCL10 in a dose-dependent manner in HRD and HRP ovarian cancer cells. An optimised olaparib concentration induced chemokine release and improved survival in the syngeneic HRD ovarian cancer mouse model but not in immunocompromised mice, likely promoting synergism of immune activation and tumour cell cytotoxicity. Overexpression of mCCL5- and mCXCL10-cleaving mDPP4 induced resistance to olaparib in the HRD mouse model. Conversely, mDPP4 inhibition led to the reversal of intrinsic PARPi resistance in the HRP mouse model. CONCLUSIONS: This study highlights the immune system-activating properties of PARP inhibitors and suggests harnessing these for effective PARPi therapy in ovarian cancer, especially in the context of HRP disease.