Macrophages Mediate Response to PARP Inhibitor Treatment in Homologous Recombination-Proficient High-Grade Serous Ovarian Cancer


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Josip Vrancic, Susan Mason, Suzanne Dowson, Anna Kilbey, Sergio Lilla, Sara Zanivan, Iain McNeish, Karen Blyth, Seth Coffelt, Patricia Roxburgh

Abstract

Background

High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy worldwide. While initially designed to target homologous recombination deficient (HRD) HGSOC, the benefit of PARP inhibitors (PARPi) extends to HR-proficient (HRP) HGSOC. This suggests a contribution of the immune microenvironment to PARPi response in HRP HGSOC.

Method

ID8-Trp53—/—;Brca1—/— and ID8-Trp53—/— cells were injected intraperitoneally into syngeneic immunocompetent mice to model HRD and HRP disease, respectively. Mice bearing orthotopic ID8 tumours were treated with niraparib and a colony-stimulating factor 1 receptor (CSF-1R) inhibitor, alone or in combination. Mice were sacrificed at humane clinical endpoint. Proteomic analysis of bulk tumour samples was performed using mass spectrometry. The abundance and phenotype of immune cells was assessed by immunohistochemistry and flow cytometry.  

Results

Niraparib treatment prolonged survival of mice bearing both ID8-Trp53—/—;Brca1—/—  (by 22 days, p=0.02) and ID8-Trp53—/— cells (by 7.5 days, p=0.03), whereas CSF-1Ri failed to affect survival of either model. When combination treatment was given, survival was similar to niraparib alone in the HRD model. However, niraparib with CSF-1Ri reversed the survival benefit observed with niraparib alone in the HRP model, indicating that macrophages are required for the efficacy of niraparib. We found macrophage abundance is similar between niraparib-treated mice and controls, while maturation markers MHC-II and CD80 are increased on macrophages from niraparib-treated tumours. Proteomic analysis revealed enrichment of phagocytosis related gene ontology biological processes in PARPi-treated mice.

Conclusion

Tumour-associated macrophages are required for response to PARPi in a HRP HGSOC mouse model, and dispensable in a HRD model. Current efforts are underway to understand how macrophages contribute to niraparib efficacy.

Impact statement

Our study indicates macrophages may be mediating the response to targeted therapies in some ovarian cancer patients. Understanding the mechanisms underlying these findings may help us identify new combination therapies or prognostic markers of response.