BRCA1 and BRCA2 deficient tumour models generate distinct ovarian tumour microenvironments and differential responses to therapy

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 in...

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Vydáno v:	Journal of ovarian research Ročník 16; číslo 1; s. 231 - 16
Hlavní autoři:	Farokhi Boroujeni, Salar, Rodriguez, Galaxia, Galpin, Kristianne, Yakubovich, Edward, Murshed, Humaira, Ibrahim, Dalia, Asif, Sara, Vanderhyden, Barbara C.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 28.11.2023 BioMed Central Ltd Springer Nature B.V BMC
Témata:	Analysis Angiogenesis Animals B7-H1 Antigen - genetics BRCA mutations BRCA1 protein BRCA1 Protein - genetics BRCA2 protein BRCA2 Protein - genetics Breast cancer Cancer Cancer therapies Care and treatment Cell death Clinical trials DNA damage DNA repair Female Genes, BRCA2 Genomes Gynecology Humans Immune checkpoint inhibitors Immunomodulation Immunotherapy Inflammation Medical prognosis Medicine Medicine & Public Health Mice Monoclonal antibodies Mutation Ovarian cancer Ovarian Neoplasms - drug therapy Ovarian Neoplasms - genetics Ovarian Neoplasms - metabolism PARP inhibitors PD-L1 protein Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use Reproductive Medicine RNA Survival Tumor microenvironment Tumor Microenvironment - genetics Tumors Immune checkpoint inhibitors mutations PARP inhibitors Ovarian cancer BRCA mutations
ISSN:	1757-2215, 1757-2215
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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1757-2215 1757-2215
DOI:	10.1186/s13048-023-01313-z