Patient-derived functional immuno-oncology platform identifies responders to ATR inhibitor and immunotherapy combinations in ovarian cancer

Nagaraj, A. S.; Salko, M.; Sirsikar, A.; Erkan, E. P.; Pietilä, E. A.; Niemiec, I.; Bao, J.; Marchi, G.; Szabo, A.; Nowlan, K.; Pikkusaari, S.; Kanerva, A.; Tapper, J.; Koivisto-Korander, R.; Kauppi, L.; Hautaniemi, S.; Vähärautio, A.; Tang, J.; Haltia, U.-M.; Kekäläinen, E.; Virtanen, A.; Salo, T.; Färkkilä, A.

doi:10.1101/2024.02.15.579904

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bioRxiv · 10.1101/2024.02.15.579904

Patient-derived functional immuno-oncology platform identifies responders to ATR inhibitor and immunotherapy combinations in ovarian cancer

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Abstract

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.

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Nagaraj, A. S., Salko, M., Sirsikar, A., Erkan, E. P., Pietilä, E. A., Niemiec, I., Bao, J., Marchi, G., Szabo, A., Nowlan, K., Pikkusaari, S., Kanerva, A., Tapper, J., Koivisto-Korander, R., Kauppi, L., Hautaniemi, S., Vähärautio, A., Tang, J., Haltia, U.-M., Kekäläinen, E., Virtanen, A., Salo, T., Färkkilä, A.. 2024-02-19. Patient-derived functional immuno-oncology platform identifies responders to ATR inhibitor and immunotherapy combinations in ovarian cancer. https://doi.org/10.1101/2024.02.15.579904

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