<i>Ex Vivo</i> Immuno-Oncology Platform Reveals Spatial T-cell Infiltration Patterns Linked to ATR Inhibition Responses in High-Grade Serous Ovarian Cancer

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.

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Journal
Cancer Immunology Research
Published
2026-01-21
DOI
https://doi.org/10.1158/2326-6066.cir-25-0743
Primary Topic
Single-cell and spatial transcriptomics
Type
article
Field-Weighted Citation Impact
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article

Ex Vivo Immuno-Oncology Platform Reveals Spatial T-cell Infiltration Patterns Linked to ATR Inhibition Responses in High-Grade Serous Ovarian Cancer

Iga Niemiec, Anastasia Lundgren, María Mercedes Hincapié-Otero, Heini Lassus et al.
Cancer Immunology Research
Single-cell and spatial transcriptomics
article

Ex Vivo Immuno-Oncology Platform Reveals Spatial T-cell Infiltration Patterns Linked to ATR Inhibition Responses in High-Grade Serous Ovarian Cancer

Iga Niemiec, Anastasia Lundgren, María Mercedes Hincapié-Otero, Heini Lassus, Jie Bao, Ulla-Maija Haltia, Joonas Jukonen, Sampsa Hautaniemi, Johanna Tapper, Riitta Koivisto-Korander, Matilda Salko, Liisa Kauppi, Giovanni Marchi, Ziqi Kang, Erdoğan Pekcan Erkan, Kirsten Nowlan, Anni Virtanen, Sanna Pikkusaari, Elina Pietilä, Anna Vähärautio, Anniina Färkkilä, Eliisa Kekäläinen, Aditi Sirsikar, Prof. Tuula Salo, Anna Kanerva, Ashwini Sakrepatna Nagaraj, Jing Tang, Angéla Szabó
article en

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.

Cancer Immunology Research
University of Helsinki (FI), Tampere University of Applied Sciences (FI), Oulu University Hospital (FI), Helsinki University Hospital (FI), Finnish Cancer Registry (FI), Tampere University Hospital (FI), Tampere University (FI), Institute for Molecular Medicine Finland (FI), Cancer Society of Finland (FI), Hospital District of Helsinki and Uusimaa (FI), Oulu University of Applied Sciences (FI), University of Oulu (FI)
Helsingin Yliopisto, European Commission, Sigrid Juséliuksen Säätiö, Syöpäjärjestöt, Biocenter Finland, Helsinki Institute of Life Science, Helsingin Yliopisto
Good health and well-being
Openalex Percentile: Top 83%
Single-cell and spatial transcriptomics
DOIOpen Access PDFOpenAlex
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