Abstract Identifying new therapeutic approaches in high-grade serous ovarian cancer (HGSC) requires the development of more accurate preclinical models that replicate the patient-specific tumor and its microenvironment. To address this, we established immunocompetent patient-derived cultures (iPDCs) for HGSC, cultured on a physiologically relevant human omentum-gel matrix. We developed a high-throughput platform that combines drug testing, histological analysis, genomic profiling, single-cell studies, and spatial biomarker discovery. Our results from 47 tumors showed that iPDCs recapitulated the tumor genomic and histological characteristics, while also retaining the intratumoral immune cells. The iPDC treatment responses correlated significantly with the patients’ clinical treatment responses. Using iPDCs and scRNAseq, we identified potentially effective therapeutic options for patients with recurrent HGSC linked to distinct tumor cell states and mechanisms of resistance. High-throughput drug response profiling with single cell-imaging identified ataxia telangiectasia and Rad3-related inhibitor (ATRi) combined with an immunotherapy targeting Autotaxin as a promising new combination treatment for HGSC. Using hyperplexed imaging and the spatial analysis, we discovered that ATRi responses were associated with significant increases in both intra- and peritumoral T cell infiltration, particularly in PD1+ CD8+ T cells. Additionally, the ATRi induced reactivation of CD8+ T cells was linked to spatial interactions with replication stress positive tumor cells. Thus, our iPDC platform presents as a representative high-throughput ex vivo model to advance precision oncology in HGSC uncovering ATRi-immunotherapy combination as a potentially effective therapeutic option for clinical translation.
Nagaraj et al. (Wed,) studied this question.