Recapitulating physiologically relevant oxygen levels and extracellular matrix remodeling in patient-derived tumor-immune tunable models reveal targeting opportunities for immunologically cold high-grade serous tumors

Abstract

High-grade serous tumors are immunologically cold, characterized by limited immune cell infiltration and reduced clinical outcome, primarily due to hypoxia and extensive extracellular matrix remodeling that disrupt tumor-stromal-immune interactions. However, current experimental models fail to fully capture oxygen and matrix microenvironmental features, limiting progress in understanding tumor-immune dynamics and developing effective treatments. Here, we demonstrate that patient-derived tumor-immune tunable models, mimicking physiologically relevant oxygen levels and extracellular matrix remodeling, recapitulate the hypoxia-induced stromal/matrix dysregulation, which causes impaired immune infiltration, and enable dissecting targeted opportunities via TGF-{beta} signaling. The models integrate cancer cells co-cultured with cancer-associated fibroblasts and exposed to immune cells as multi-culture or challenged them to infiltrate into a 3D model bioengineered with autologous plasma from the matching patient or onto decellularized human ovaries. By bioengineering physiologically relevant oxygen levels of hypoxic tumors and physoxic ovaries, we uncovered that intratumoral hypoxia acts as a friend and a foe, causing hypoxia-induced stromal-driven impaired immune infiltration but enhancing the activation and cytotoxicity of CD8+ T cells. We also showed that targeting TGF-{beta} signaling reversed the hypoxia-induced stromal-driven impaired immune infiltration. These human-relevant tunable models may aid the development of targeted therapies to turn immunologically cold tumors into hot ones.