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Characterizing the Tumor Immune Microenvironment of Syngeneic Mouse Models of Ovarian Cancer to Predict Response to PD-L1 blockade

ABSTRACT: Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer with an imperative need for new treatments. Immunotherapy has had marked success in some cancer types; however, clinical trials studying the efficacy of immune checkpoint inhibitors for the treatment of EOC provided benefit in <15% of patients. EOC is a particularly complex cancer since it develops from various tissues in the reproductive tract and metastasizes into the peritoneal cavity where it is able to colonize almost all organs, creating different tumor microenvironments (TME) containing a variety of immune profiles. In this study, we assessed the immune composition of different murine syngeneic models of EOC from different cellular origins (ovarian and fallopian tube epithelium) and harboring known mutations relevant to human disease, including TP53 mutation, PTEN suppression, and constitutive KRAS activation. We determined immunogenicity of multiple tumor models in vivo, the T and myeloid profile of orthotopic tumors and the immune composition of ascites, by flow cytometry, IHC and single cell RNA-sequencing. Our findings allowed us to predict which models might respond best to PD-L1 blockage, according to key characteristics such as tumor immunogenicity, MHC status, and T cell infiltration. Together these data highlight the heterogeneity found in murine EOC, as in human disease, identified features that might predict immune checkpoint inhibitor efficacy, and revealed crucial information about differences between murine models in the TME composition vs. ascites fluid. These data provide a solid foundation for selecting models in future testing of immunotherapies according to the immune composition and tumor characteristics.

ORGANISM(S): Mus musculus

PROVIDER: GSE183368 | GEO | 2022/06/01

REPOSITORIES: GEO

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Project description:Background: In previous studies we showed that IL-27 shares several effects with IFN-γ in human cancer cells. To identify novel extracellular mediators, potentially involved in epithelial ovarian cancer (EOC) biology, we analyzed the effect of IL-27 or IFN-γ on the secretome of EOC cells in culture. Methods: The secretome of cytokine-treated or untreated SKOV3 cells was analyzed by nano-UHPLC-MS/MS and eluting peptides by an Orbitrap Fusion Tribrid mass spectrometer. Extracellular GBP1 was studied by ELISA, immunoprecipitation, GTP-agarose pull-down, and Western blotting. GBP and STAT proteins were analysed on cell lysates by Western blot. GBP1 was transfected using lipofectamine reagent and cell viability measured by MTT assay. Results: IL-27 and IFN-γ modulate the extracellular release of a limited fraction of proteins that were also induced in the whole cell. Among these proteins we focused our attention on GBP1, a guanylate-binding protein and GTPase, which is a mediator of several biological activities of IFNs. Interestingly GBP1, 2, and 5 were induced by cytokine treatment in EOC cells, but only GBP1 was secreted. ELISA and immuno-blotting analyses showed that cytokine-stimulated EOC cells release full-length GBP1 molecule in vitro, through non-classical pathways, not involving microvesicles. Moreover, soluble, full-length GBP1 accumulates in the ascites of most EOC patients, suggesting a potential role of extracellular GBP1 in the tumor environment. EOC cells enriched from ascites showed constitutive tyrosine-phosphorylated STAT1 and STAT3 proteins and GBP1 expression, supporting a role of STAT-activating cytokines in GBP1 induction in vivo. Data from the TCGA dataset of EOC indicate that high GBP1 gene expression correlates with a better overall survival. Accordingly GBP1 transfection reduced SKOV3 cell proliferation, suggesting a potential anti-tumor activity of GBP1. Conclusions: Our data show for the first time that soluble GBP1 is released by cytokine-stimulated EOC cells in vitro and accumulates in EOC patients’ ascites. GBP1 expression may have anti-tumor effects, in EOC, as suggested by TCGA dataset analysis and in vitro transfection experiments. Further studies to identify the biological role of soluble GBP1 in the tumor environment of EOC are warranted.

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Characterizing the Tumor Immune Microenvironment of Syngeneic Mouse Models of Ovarian Cancer to Predict Response to PD-L1 blockade

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