Patient-derived functional immuno-oncology platform identifies responders to ATR inhibitor and immunotherapy combinations in ovarian cancer
Responses to single agent immunotherapies have remained modest in high-grade serous ovarian cancer (HGSC), suggesting the need for combination treatments. Identifying clinically effective immunotherapy combinations (IC) requires pre-clinical testing using models representing the patient-specific immune microenvironment. Here, we established a functional immuno-oncology platform for high-throughput and functional testing of IC using HGSC patient-derived immunocompetent cultures (iPDCs) established on patient-derived omentum gel matrix. We employed genomic and single-cell analysis to assess the intricate and functional characteristics of the iPDCs combined with tumor and immune cell-specific cytotoxic responses. Corroborating the clinical response to Poly (ADP-ribose) polymerase inhibitors (PARPi), iPDCs showed homologous recombination deficiency (HRD) - specific response to PARPi. Importantly, drug responses from iPDCs of chemotherapy and PARPi refractory patients corresponded with patient outcomes and aligned with distinct pathway activities from single-cell RNA sequencing analysis. Furthermore, iPDCs from HRD tumors showed response to anti-PD1 antibody as measured by decrease in tumor cells combined with augmented T cell activation. High-throughput drug testing followed by single cell-imaging from iPDCs revealed patient-specific responses to combination of ataxia telangiectasia and Rad3-related inhibitor (ATRi) with DNA damaging agents or immunotherapies. Integration of cytotoxic responses with immune cell states uncovered patient-specific immune activation with the combination of ATRi and a novel immunotherapy targeting Autotaxin (ATX), and this response was significantly associated with a tumor-cell replication stress biomarker in single-cell analysis of tCycIF highly multiplexed imaging. In conclusion, iPDCs provide a platform for high-throughput screening and functional testing of immuno-oncology agents for precision oncology in HGSC.