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

Abstract

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. Here, using syngeneic OvCa models and genetic and pharmacologic perturbations, we discovered that losartan - a widely prescribed anti-hypertensive drug - exhibits dual effects on both the tumor microenvironment and cancer cells to sensitize OvCa to chemo-immunotherapy. Specifically, losartan treatment i) reprograms the tumor microenvironment 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 (less than $1-2/day) of losartan warrant rapid translation of our findings to patients with OvCa.