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BRCA1 and BRCA2 deficient tumour models generate distinct ovarian tumour microenvironments and differential responses
Salar Farokhi Boroujeni1,2, Galaxia Rodriguez1,2, Kristianne Galpin1,2
1Cancer Therapeutics Program, Ottawa Hospital Research Institute, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada.
Abstract:
Clinical trials are currently exploring combinations of PARP inhibitors and immunotherapies for the treatment of ovarian cancer, but their effects on the ovarian tumour microenvironment (TME) remain unclear. Here, we investigate how olaparib, PD-L1 monoclonal antibodies, and their combination can influence TME composition and survival of tumour-bearing mice. We further explored how BRCA deficiencies can influence the response to therapy. Olaparib and combination therapies similarly improved the median survival of Brca1- and Brca2-deficient tumour-bearing mice. Anti-PD-L1 monotherapy improved the survival of mice with Brca1-null tumours, but not Brca2-null tumours. A detailed analysis of the TME revealed that olaparib monotherapy resulted in a large number of immunosuppressive and immunomodulatory effects in the more inflamed Brca1-deficient TME but not Brca2-deficient tumours. Anti-PD-L1 treatment was mostly immunosuppressive, resulting in a systemic reduction of cytokines and a compensatory increase in PD-L1 expression. The results of the combination therapy generally resembled the effects of one or both of the monotherapies, along with unique changes observed in certain immune populations. In-silico analysis of RNA-seq data also revealed numerous differences between Brca-deficient tumour models, such as the expression of genes involved in inflammation, angiogenesis and PD-L1 expression. In summary, these findings shed light on the influence of novel therapeutics and BRCA mutations on the ovarian TME.
Insights
PARP inhibitors and PD-L1 blockade impact ovarian cancer's tumor microenvironment (TME). BRCA deficiencies influence responses, with combination therapy showing survival benefits in Brca1/Brca2-deficient mice.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Ovarian cancer treatment explores PARP inhibitors and immunotherapy combinations.
- The impact of these treatments on the ovarian tumor microenvironment (TME) is not fully understood.
- BRCA mutations are key factors in ovarian cancer development and treatment response.
Purpose of the Study:
- To investigate the effects of olaparib, PD-L1 antibodies, and their combination on the ovarian TME.
- To explore how BRCA deficiencies influence the response to these novel therapies.
- To analyze survival outcomes in tumor-bearing mice.
Main Methods:
- Treatment of tumor-bearing mice with olaparib, anti-PD-L1, or combination therapy.
- Detailed analysis of tumor microenvironment composition.
- In-silico analysis of RNA-seq data to assess gene expression differences.
Main Results:
- Olaparib and combination therapies improved survival in both Brca1- and Brca2-deficient mice.
- Anti-PD-L1 monotherapy improved survival only in Brca1-null tumors.
- Olaparib induced immunosuppressive effects in Brca1-deficient TME but not Brca2-deficient tumors.
- Anti-PD-L1 treatment led to systemic immunosuppression and increased PD-L1 expression.
- Combination therapy showed varied effects, resembling monotherapies with unique immune changes.
- In-silico analysis revealed distinct gene expression profiles related to inflammation, angiogenesis, and PD-L1 in Brca-deficient models.
Conclusions:
- Olaparib, PD-L1 blockade, and their combination differentially affect the ovarian TME based on BRCA mutation status.
- BRCA deficiencies significantly influence the response to these therapies.
- Findings provide insights into novel therapeutic strategies for ovarian cancer, considering BRCA status and TME modulation.
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