Patient-derived model capturing hypoxia and extracellular matrix remodelling of immunologically cold high-grade serous tumours

Abstract

Abstract High-grade serous carcinoma tumours present poor survival rates, often associated with immunologically excluded environments driven by hypoxia and extensive extracellular matrix remodelling that disrupt tumour-stromal-immune interactions. Current experimental models fail to fully capture these microenvironmental features, limiting understanding of tumour-immune dynamics and drug development. Here, we present bioengineered patient-derived tumour-immune models to mimic physiologically relevant oxygen levels and extracellular matrix remodelling. Cancer cells are co-cultured with cancer-associated fibroblasts within human plasma-3D matrices or grown on decellularized human ovaries. Immune cells are either included within the 3D constructs to study multi-cellular interactions or challenged to infiltrate the matrices. We demonstrate that intratumoural hypoxia acts as a friend and a foe enhancing the activation and cytotoxicity of CD8 + T cells while inducing stromal/matrix dysregulation associated with impaired immune infiltration. Targeting TGF-β signalling attenuates the hypoxia-driven stromal-mediated immune exclusion. These relevant models may aid the development of targeted therapies to transform immunologically cold tumours into immunogenic to benefit female patients.