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Nanostring transcriptomic analysis of lungs from antiChemR23 treated and untreated 4T1-bearing mice

ABSTRACT: Macrophages are a major component of the tumor environment and their accumulation often correlates with poor prognosis and resistance to anticancer treatments. In this study, we thus investigated the therapeutic interest to target ChemR23, a receptor of the resolution of inflammation, in cancers using an agonist monoclonal antibody, antiChemR23. In vitro experiments on M2-like macrophages treated by antiChemR23 agonist decreased their inflammatory phenotype. In vivo, treatment with antiChemR23 agonist increased mouse survival and decreased metastasis occurrence in a model of triple-negative breast cancer in correlation with modulation of TAM phenotype in the metastatic niche.

ORGANISM(S): Mus musculus

PROVIDER: GSE218322 | GEO | 2023/07/17

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAM) represent an abundant cell population of the immune infiltrate in solid tumors and have been shown to orchestrate escape from immune surveillance. Macrophages display a very plastic phenotype which is recapitulated in vitro by classifying certain subsets according to exposure with defined, individual cytokines. The tumor-promoting M2 macrophages are polarized in vitro by differentiating human monocyte-derived macrophages with the T helper cell type 2 (Th2) response cytokines interleukin-4 and interleukin-13 or the immunosuppressive cytokine interleukin-10. Notably, only the latter macrophage subset undergoes apoptosis when treated with the colony stimulating factor 1 receptor (CSF1R) blocking antibody emactuzumab. However, under physiologic conditions the phenotype of TAM is shaped by a combination of cytokines. Hence, we evaluated if the addition of IL-10 to IL-4 or IL-13 differentiated macrophages is able to override IL-4/-13 mediated signaling and to restore susceptibility to emactuzumab. Though addition of IL-10 did not restore emactuzumab susceptibility, we surprisingly detected that only IL-4 differentiated macrophages sustained their specific marker expression while IL-10 skewed the IL-13 differentiated macrophage profile towards the IL-10 regulated phenotype. In-depth characterization by gene expression profiling revealed unique signatures of IL-4+IL-10 and IL-13+IL-10 differentiated macrophage subsets characterized by upregulation of the canonical NFÎºB signaling or Wnt/Î²-catenin signaling pathways, respectively. In silico-based analysis of a large cohort of cancer patients revealed distinct interleukin-4 or interleukin-13 overexpression patterns in a subset of patients with partial co-expression of IL-10 but almost absent IL-4/IL-13 co-expression. These patients may have less TAM depletion under therapy with CSF1R inhibitors. Five different macrophage subtypes were differentiated for six days with respect to different cytokines and transcriptomically profiled with three biological replicates derived from three different human, healthy volunteer donors

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Nanostring transcriptomic analysis of lungs from antiChemR23 treated and untreated 4T1-bearing mice

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