Telmisartan improves chemotherapy and immune checkpoint blockade efficacy by enhancing mitotic catastrophe and inducing tumor immunogenicity 3238

Abstract Description Mitotic catastrophe is a mechanism of cell death following aberrant mitosis and is induced by FDA-approved anti-cancer drugs, e.g., taxanes, TopII inhibitors, and select small molecules. Agents inducing mitotic catastrophe can induce STING signals and immunogenic cell death (ICD), distinct immunogenic pathways that can boost immune checkpoint blockade (ICB) efficacy. Here, we show the FDA-approved angiotensin receptor blocker telmisartan enhances chemotherapy-induced mitotic catastrophe and tumor immunogenicity. Telmisartan selectively synergizes with G2/M-acting chemotherapies and small molecules (e.g., olaparib) to augment DNA damage, G2/M arrest, and cytotoxicity significantly in vitro and in vivo. Combining telmisartan with chemotherapy induced chromosome abnormalities and prometaphase arrest consistent with mitotic catastrophe. Telmisartan boosted type I IFN production and pTBK1, indicative of increased STING activation. Consistent with these data, top altered pathways by RNAseq with telmisartan include those related to mitotic cell cycle and type I IFN production. Strikingly, while telmisartan augmented chemotherapy-induced ICD, it also induced ICD independent of DNA damage and augmented αCTLA4 ICB efficacy in vivo. In our ongoing prostate cancer trial, telmisartan reduced PSA by 68% after 4 cycles in 1 patient when added to failed olaparib. Our data support telmisartan as a rapidly clinically translatable agent to improve standard-of-care DNA damaging agents and ICB. Funding Sources Supported by NIH T32 AI138944; NCATS TL1 TR002647; NCI F31 CA281345; NIH T32GM113896; Peter Michael Foundation, Guyre Funds; Gmelich Chair Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)