Investigator
Technical University Of Munich
PARP inhibitor-induced anti-tumour chemokine response is suppressed by dipeptidyl peptidase 4 (DPP4) in ovarian cancer
Abstract 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.
CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer
Abstract Background Response to immune checkpoint blockade (ICB) in ovarian cancer remains disappointing. Several studies have identified the chemokine CXCL9 as a robust prognosticator of improved survival in ovarian cancer and a characteristic of the immunoreactive subtype, which predicts ICB response. However, the function of CXCL9 in ovarian cancer has been poorly studied. Methods Impact of Cxcl9 overexpression in the murine ID8-Trp53−/− and ID8-Trp53−/–Brca2−/− ovarian cancer models on survival, cellular immune composition, PD-L1 expression and anti-PD-L1 therapy. CXCL9 expression analysis in ovarian cancer subtypes and correlation to reported ICB response. Results CXCL9 overexpression resulted in T-cell accumulation, delayed ascites formation and improved survival, which was dependent on adaptive immune function. In the ICB-resistant mouse model, the chemokine was sufficient to enable a successful anti-PD-L1 therapy. In contrast, these effects were abrogated in Brca2-deficient tumours, most likely due to an already high intrinsic chemokine expression. Finally, in ovarian cancer patients, the clear-cell subtype, known to respond best to ICB, displayed a significantly higher proportion of CXCL9high tumours than the other subtypes. Conclusions CXCL9 is a driver of successful ICB in preclinical ovarian cancer. Besides being a feasible predictive biomarker, CXCL9-inducing agents thus represent attractive combination partners to improve ICB in this cancer entity.
The chemokine CX3CL1 promotes intraperitoneal tumour growth despite enhanced T-cell recruitment in ovarian cancer
T-cell recruiting chemokines are required for a successful immune intervention in ovarian cancer, and also for the efficacy of modern anticancer agents such as PARP inhibitors. The chemokine CX3CL1 recruits tumour-suppressive T-cells into solid tumours, but also mediates cell-cell adhesions, e.g. of tumour cells, through its membrane-bound form. So far, its role in ovarian cancer has only been rudimentarily addressed. We show that high CX3CL1 expression significantly correlates with worsened survival in human high-grade serous ovarian cancer (n=219). In preclinical ovarian cancer, CX3CL1 plays a dual role, as it enhances the adaptive anti-tumour response, but overall still promotes tumour growth, the latter as a feature of the intraperitoneal environment. Moreover, PARP inhibitors are able to increase CX3CL1 release from human ovarian cancer cells. Collectively, our study shows that CX3CL1 is a driver of intraperitoneal tumour growth in ovarian cancer, a feature that may compromise the anticancer effect of CX3CL1-inducing PARP inhibitors.
