Losartan rewires the tumor-immune microenvironment and suppresses IGF-1 to overcome resistance to chemo-immunotherapy in ovarian cancer
Ovarian cancer (OvCa) is the most lethal of the gynecologic malignancies. Immune checkpoint inhibitors, which have revolutionized the treatment of multiple malignancies, have had limited efficacy in OvCa patients. This lack of effectiveness is partly due to the abnormal ovarian tumor microenvironment (TME), displaying a desmoplastic, highly fibrotic extracellular matrix. High extracellular matrix deposition leads to a buildup of compressive forces that cause tumor blood vessel collapse, reduced vessel perfusion, poor delivery of drugs, and compromised trafficking of cytotoxic T-cells to these tumors. Using two syngeneic OvCa models, we tested the effect of losartan, a widely prescribed anti-hypertensive drug, on reprogramming the TME and chemosensitizing the cancer cells. Losartan treatment (i) reprograms the TME leading to increased vascular perfusion, and thus enhances 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. The safety and low cost ( < $1-2/day) of losartan warrant rapid translation of our findings to patients with OvCa.
Journal
British Journal of CancerAuthors
Funding
Targeting HMGB1 to improve hearing andenhance therapy for Vestibular SchwannomasTargeting HMGB1 to improve hearing andenhance therapy for Vestibular SchwannomasReprogramming PDAC tumor microenvironment to improve immunotherapyImproving treatment of HER2+ breast cancer brain metastasis by targeting lipid metabolismCo-Targeting IL-6 and EGFRsignaling for the Treatment of Schwannomatosis and Associated PainDissecting Pediatric Brain Tumor Microenvironment to Improve TreatmentAmerican Cancer Society (American Cancer Society, Inc.) Grant Mission Boost AwardU.S. Department of Defense (United States Department of Defense) Grant W81XWH-20-1-0222Reengineering obesity-induced abnormal microenvironment to improve PDAC treatmentCo-Targeting IL-6 and EGFRsignaling for the Treatment of Schwannomatosis and Associated PainReprogramming the tumormicroenvironment to improve immunotherapy of glioblastomaTargeting physical stress-driven mechanisms to overcome glioblastoma treatment resistance