Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint blockers (ICBs) and chimeric antigen receptor (CAR)-T cells—which have revolutionized the treatment of multiple malignancies—have had limited efficacy in OvCa patients. This lack of efficacy is partly due to abnormal extracellular matrix (ECM) deposition leading to a buildup of compressive forces that induce vessel collapse, hypoperfusion, poor delivery of nutrients and drugs, and compromised trafficking of cytotoxic T cells to these tumors. The resulting tumor microenvironment (TME) is also hypoxic, acidic, and immunosuppressive. Our overarching hypothesis is that losartan, an FDA-approved antihypertensive drug that blocks angiotensin signaling, can overcome these challenges by normalizing the TME to enhance the delivery and efficacy of therapies in OvCa. Retrospective study showed that treatment with angiotensin blockers is associated with a 30-month overall survival benefit in OvCa patients. In our OvCa models, losartan reduced matrix content and reopened compressed vessels. As a result, blood perfusion increased, leading to enhanced drug delivery and improved chemotherapy efficacy. Losartan also relieved lymphatic vessel collapse in the diaphragm, which increased the drainage of peritoneal fluid and reduced ascites. Using unbiased RNASeq analysis, we found that in addition to normalizing the tumor matrix and vasculature, losartan treatment also activates immune response pathways. Furthermore, losartan increases the infiltration and function of immune effector cells and improves the outcome of immunotherapy using ICBs. Our findings provide the rationale and supporting data for a clinical trial on combined losartan and immunotherapy in ovarian cancer patients.
This abstract is also being presented as Poster B75.
Citation Format: Yao Sun, Wenjianlong Zhao, David R. Spriggs, Rakesh K. Jain, Lei Xu. Reprogramming the tumor microenvironment with losartan to enhance immunotherapy of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR07.