Coordinated Blockade of TGF-β and PD-L1 Promotes Anti-Tumor Immunity in Ovarian Cancer Models

Abstract

High-grade serous ovarian cancer (HGSC) remains the deadliest gynecologic malignancy due to late-stage diagnosis and high recurrence rates. Current immune checkpoint blockade (ICB) therapies show limited efficacy in HGSC, with no approved immunotherapy options for patients. This is due to an immunosuppressive tumor immune microenvironment (TIME) that limits the efficacy of ICB. Resistance to immunotherapy is driven in part by TGF-β signaling in the ovarian TIME, leading to immune suppression, metastasis, and development of malignant ascites. Bintrafusp alfa (BA) is a bifunctional fusion protein designed to simultaneously block TGF-β and PD-L1 pathway signaling by localizing to the TIME with high PD-L1 expression. The therapeutic impact of BA was evaluated in two syngeneic HGSC tumor engraftment models derived from ovarian surface epithelium of mice. BA treatments controlled ascites development and induced anti-tumor immune skewing of macrophages, NK cells, and T effector memory cells, corresponding with long-term immunological memory responses. BA treatments enhanced cytotoxicity that was traced back to resident memory T cells and decreased suppressive Gata6+ large peritoneal macrophages in the tumor, thus reshaping the tumor immune landscape in HGSC. These findings show that BA treatments can overcome immunotherapy resistance in preclinical HGSC models and promote anti-tumor immunity. This work informs the design of future multi-pronged therapeutic strategies and provides rationale for clinical translation to clinical trials with patient stratification.