Abstract 2745: Murine high grade serous ovarian cancer (HGSOC) models replicate the human tumor microenvironment and suggest anti-tumor activities of macrophages after chemotherapy

Abstract

Abstract The aim of this study is to characterize and validate similarities between the human tumor microenvironment (TME) and the TME of new HGSOC murine models and to use the models to analyze the role of tumor associated macrophages (TAMs) after chemotherapy. HGSOC has seen in the past decades only a modest reduction of mortality. This is in part due to the lack of suitable models, as the origin and mutation patterns of HGSOC were not previously understood. Despite recent advances with organoid models, murine models that represent the TME and in particular the complex interactions with the immune system are needed. We characterized the TME of six orthotopic, transplantable syngeneic murine HGSOC lines established from tumors in genetic models and compared these to patient biopsies. This analysis identified significant correlations between the transcriptome, host cell infiltrates, immune response, matrisome, vasculature and tissue modulus of mouse and human TMEs, with several stromal and malignant cell targets in common. However, each model also showed distinct differences and potential vulnerabilities that will enable us to study potential therapies. These models allowed us to extend our understanding of the role of TAMs following chemotherapy. Chemotherapy reduced the number and changed the phenotype of TAMs both in patient biopsies and in mouse models. Following chemotherapy, inflammasome activation in TAMs was also observed. Depletion of TAMs with CSFR1 inhibitors after carboplatin treatment reduced survival in a mouse model, suggesting that chemotherapy can activate sub-populations of macrophages to an anti-tumor phenotype that can sustain adaptive immunity. In conclusion, we have characterized murine transplantable models that share similarities with human HGSOC and have helped us elucidate the anti-tumor role of TAMs once activated by chemotherapy. Citation Format: Chiara Berlato, Owen Heath, Eleni Maniati, Ganga Gopinathan, Panoraia Kotantaki, Samar Elorbany, Jacqueline McDermott, Colin Pegrum, Ludmila Szabova, Ruth Perets, Ronny Drapkin, Peter Bailey, Alessandro Annibaldi, Desmond P. Barton, Frances R. Balkwill. Murine high grade serous ovarian cancer (HGSOC) models replicate the human tumor microenvironment and suggest anti-tumor activities of macrophages after chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2745.