Abstract A104: Losartan rewires ovarian cancer tumor-immune microenvironment and suppresses IGF-1 to amplify chemo-immunotherapy sensitivity

Abstract

Abstract Background: Ovarian Cancer (OvCa) is the most lethal gynecologic malignancy worldwide. The use of immune checkpoint inhibitors (ICIs) has revolutionized the therapy of several malignancies. Unfortunately, ICIs have had limited efficacy in OvCa, with objective response rates in only 10 to 15% of patients. Prevailing preclinical and clinical data indicate that abnormalities in the tumor microenvironment (TME) contribute to immunosuppression and dictate the outcome of ICIs. OvCa harbors an abnormal TME, characterized by a desmoplastic extracellular matrix with high collagen levels. The accumulation of extracellular matrix components gives rise to increased compressive forces within the tumor, leading to blood vessel collapse and vessel perfusion reduction, causing impaired drug delivery and compromised trafficking of cytotoxic T-cells. The resulting TME is hypoxic and immunosuppressive. In our attempts to normalize the TME, we discovered that angiotensin II receptor 1 (AT1) is a key regulator of compressive solid stress. We showed in OvCa models that treatment with losartan – a widely prescribed anti-hypertensive drug – reduced matrix content and re-opened compressed vessels. As a result, blood perfusion increased, leading to enhanced drug delivery and improved chemotherapy efficacy. Furthermore, our retrospective analysis demonstrated that treatment with angiotensin blockers is associated with a 30-month overall survival benefit in OvCa patients. As a natural extension of this study, we are now asking the question: Can losartan reprogram the immunosuppressive TME of OvCa to enhance immunotherapy alone or with chemotherapy? Methods and Results: Here, using two syngeneic immunocompetent OvCa models and genetic and pharmacologic perturbations, we discovered that losartan – a widely prescribed anti-hypertensive drug – exhibits dual effects on both the TME and cancer cells to sensitize OvCa to chemo-immunotherapy. Specifically, losartan treatment i) reprograms the TME, leading to increased vascular perfusion, and thus enhances ICI drug delivery and immune effector cell intratumoral infiltration and function; and ii) rewires the OvCa cells by suppressing the IGF-1 signaling, resulting in enhanced chemosensitivity. As a result of the combined tumor and stromal effects, losartan treatment enhances the efficacy of chemo-immunotherapy in OvCa models. Conclusions: Two of the greatest problems in ovarian cancer are chemotherapy resistance and the failure of immunotherapeutics to successfully alter the course of patients with OvCa. Our study offers a novel combination treatment strategy that can potentially enhance chemo-immunotherapy efficacy. As one of the most prescribed drugs for hypertension, the safety and low cost (less than $1-2/day) of losartan warrants rapid translation of our research to patients with OvCa. Citation Format: Yao Sun, Zhenzhen Yin, Limeng Wu, Changli Yue, Sonu Subudhi, Pinji Lei, Alona Muzikansky, Bo R. Rueda, Lei Xu. Losartan rewires ovarian cancer tumor-immune microenvironment and suppresses IGF-1 to amplify chemo-immunotherapy sensitivity [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A104.