Telmisartan increases olaparib efficacy in homologous recombination proficient tumors by augmenting type I interferon production.

BACKGROUND: Poly-ADP ribose polymerase inhibitors (PARPi) are well-known to treat tumors that are deficient in homologous recombination (HR) DNA repair. However, PARPi can treat breast cancer gene (BRCA) wild-type tumors, the mechanisms behind which are not fully elucidated. We previously reported that tumor-intrinsic programmed death ligand-1 (PD-L1) signals promote HR, and that genetic tumor PD-L1(KO) impairs HR and sensitizes tumors to PARPi. Despite significant PARPi efficacy in PD-L1(KO) tumors, US Food and Drug Administration (FDA)-approved anti-PD-L1 antibodies did not improve PARPi. Thus, additional clinically translatable approaches to target tumor-intrinsic PD-L1 signals to elicit PARPi sensitivity are needed. METHODS: We used control and genetically modified murine and human tumor cell lines to demonstrate signaling outcomes and treatment efficacy of olaparib and telmisartan alone or combined in vitro with immunoblots, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability assays, and quantitative reverse transcription-PCR (qRT-PCR). We tested treatment efficacy changes in the tumor immune microenvironment and immune treatment mechanisms in vivo using transplantable murine cancer models and flow cytometry. RESULTS: The FDA-approved angiotensin II receptor blocker (ARB) antihypertensive telmisartan depleted tumor PD-L1, synergized with PARPi, and augmented PARPi-induced DNA damage. Surprisingly, telmisartan improved PARPi independently of tumor PD-L1, which expands telmisartan applicability to improve PARPi in PD-L1(-) tumors. Telmisartan was the only ARB tested that depleted tumor PD-L1 and synergized with PARPi, suggesting that PARPi synergy in tumor cells is not an ARB class effect but is unique to telmisartan. Telmisartan potently increased cytosolic DNA and immunogenic tumor stimulator of interferon genes (STING) signals, including type I interferon (IFN-I) production, when combined with PARPi. Consistent with these data, telmisartan potently improved PARPi efficacy in vivo, but its efficacy was abolished by eliminating tumor STING or all IFN-I signals. IFN-I blockade suppressed antitumor immunity in combination-treated tumors, supporting STING-induced IFN-I as a mechanism for improved antitumor immunity in combination-treated tumors. CONCLUSIONS: Telmisartan depletes tumor PD-L1 but has significant PD-L1-independent clinical translational potential to improve PARPi in BRCA wild-type (WT) tumors and augment tumor immunogenicity.