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Updated: Jun 5, 2025
An Orthotopic Model of Serous Ovarian Cancer in Immunocompetent Mice for in vivo Tumor Imaging and Monitoring of Tumor Immune Responses
Published on: November 28, 2010
Integrated immunogenomic analyses of high-grade serous ovarian cancer reveal vulnerability to combination
Raphael Gronauer1, Leonie Madersbacher1, Pablo Monfort-Lanzas1,2
1Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
Background:
The efficacy of immunotherapies in high-grade serous ovarian cancer (HGSOC) is limited, but clinical trials investigating the potential of combination immunotherapy including poly-ADP-ribose polymerase inhibitors (PARPis) are ongoing. Homologous recombination repair deficiency or BRCAness and the composition of the tumor microenvironment appear to play a critical role in determining the therapeutic response.
Methods:
We conducted comprehensive immunogenomic analyses of HGSOC using data from several patient cohorts. Machine learning methods were used to develop a classification model for BRCAness from gene expression data. Integrated analysis of bulk and single-cell RNA sequencing data was used to delineate the tumor immune microenvironment and was validated by immunohistochemistry. The impact of PARPi and BRCA1 mutations on the activation of immune-related pathways was studied using ovarian cancer cell lines, RNA sequencing, and immunofluorescence analysis.
Results:
We identified a 24-gene signature that predicts BRCAness. Comprehensive immunogenomic analyses across patient cohorts identified samples with BRCAness and high immune infiltration. Further characterization of these samples revealed increased infiltration of immunosuppressive cells, including tumor-associated macrophages expressing TREM2, C1QA, and LILRB4, as specified by single-cell RNA sequencing data and gene expression analysis of samples from patients receiving combination therapy with PARPi and anti-PD-1. Our findings show also that genomic instability and PARPi activated the cGAS-STING signaling pathway in vitro and the downstream innate immune response in a similar manner to HGSOC patients with BRCAness status. Finally, we have developed a web application (https://ovrseq.icbi.at) and an associated R package OvRSeq, which allow for comprehensive characterization of ovarian cancer patient samples and assessment of a vulnerability score that enables stratification of patients to predict response to the combination immunotherapy.
Conclusions:
Genomic instability in HGSOC affects the tumor immune environment, and TAMs play a crucial role in modulating the immune response. Based on various datasets, we have developed a diagnostic application that uses RNA sequencing data not only to comprehensively characterize HGSOC but also to predict vulnerability and response to combination immunotherapy.
Insights
This study identifies a 24-gene signature predicting BRCAness in high-grade serous ovarian cancer (HGSOC). It reveals how genomic instability and PARP inhibitors impact the tumor immune microenvironment, aiding immunotherapy response prediction.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Immunotherapy efficacy in high-grade serous ovarian cancer (HGSOC) is limited.
- Homologous recombination repair deficiency (BRCAness) and tumor microenvironment influence therapeutic response.
- Combination immunotherapy with poly-ADP-ribose polymerase inhibitors (PARPis) is under investigation.
Purpose of the Study:
- To conduct comprehensive immunogenomic analyses of HGSOC.
- To develop a machine learning model for predicting BRCAness from gene expression data.
- To characterize the tumor immune microenvironment and its response to PARPi and immunotherapy.
Main Methods:
- Machine learning for BRCAness classification from gene expression data.
- Integrated analysis of bulk and single-cell RNA sequencing for immune microenvironment delineation.
- In vitro studies on the impact of PARPi and BRCA1 mutations on immune pathways.
Main Results:
- A 24-gene signature predictive of BRCAness was identified.
- BRCAness samples showed increased infiltration of immunosuppressive tumor-associated macrophages (TAMs).
- Genomic instability and PARPi activated the cGAS-STING pathway, mimicking BRCAness innate immune response.
Conclusions:
- Genomic instability and TAMs significantly modulate the HGSOC immune environment.
- A diagnostic application (OvRSeq) was developed to characterize HGSOC and predict response to combination immunotherapy.
