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Endothelial Rbpj is essential for the education of tumor-associated macrophages

ABSTRACT: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological cancers worldwide. EOC cells educate tumor-associated macrophages (TAMs) through CD44-mediated cholesterol depletion to generate an immunosuppressive tumor microenvironment (TME). In addition, tumor cells frequently activate Notch1 receptors on endothelial cells (ECs) to facilitate metastasis. However, little is known whether the endothelium would also influence the education of recruited monocytes. Here, we report that canonical Notch signaling through RBPJ in ECs is an important player in the education of TAMs and EOC progression. Deletion of Rbpj in the endothelium of adult mice reduced infiltration of monocyte-derived macrophages into the TME of EOC and prevented the acquisition of a typical TAM gene signature. This was associated with stronger cytotoxic activity of T cells and decreased tumor burden. Mechanistically, we identified CXCL2 as a novel Notch/RBPJ target gene. This angiocrine factor regulates the expression of CD44 on monocytes and subsequent cholesterol depletion of TAMs. Bioinformatic analysis of ovarian cancer patient data showed that increased CXCL2 expression is accompanied by higher expression of CD44 and TAM education. As such, EOC cells employ the tumor endothelium to secrete CXCL2 in order to facilitate an immunosuppressive microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE213371 | GEO | 2022/09/15

REPOSITORIES: GEO

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Project description:Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) which can either promote tumor progression (M2) or induce antitumor immunity (M1). The hypothesis of our study is that the expression of FOLR2 is associated with an M2-like macrophage profile. The main goal of this study is to compare the transcriptomic profile of FOLR2 positive and FOLR2 negative TAMs obtained from the ascites of C57BL/6 mice bearing ovarian ID8 intraperitoneal tumors. Abstract: The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Selective targeting of the pro-tumorigenic subset of TAMs represents an attractive therapeutic strategy. Here, we demonstrate that a subset of TAMs that expressing folate receptor β (FRβ) possess an immunosuppressive, tumor-promoting M2-like profile, while FRβ negative TAMs feature pro-inflammatory M1 macrophage properties. In syngeneic tumor mouse models, the administration of FRβ-targeted chimeric antigen receptor (CAR) T-cells mediated elimination of FRβ+ TAMs in the TME, which resulted in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8+ T-cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR T-cells also improved the effectiveness of tumor-directed anti-mesothelin CAR T-cells, while simultaneous co-administration of both CAR products did not. Thus, CAR T-cell-mediated depletion of immunosuppressive M2-like TAMs incites a pro-inflammatory TME that broadens endogenous antitumor immunity and limits tumor progression, highlighting the pro-tumor role of FRβ+ TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.

Project description:High-grade gliomas, the most common and aggressive primary brain tumors, are characterized by a complex and multifaceted tumor microenvironment (TME). Among the non-malignant cells of the glioma TME, tumor-associated microglia and macrophages (TAMs) constitute the major compartment. In patients, a greater abundance of TAMs is associated with high-grade and more aggressive disease. In a range of glioma mouse models, we have observed specific alterations in TAM dynamics and functions during tumor development and following different therapeutic interventions, including irradiation. The underlying TAM abundance may also modulate the subsequent response to TAM-targeted therapy, including the anti-CSF1R inhibitor BLZ945, which results in a pronounced tumor regression in different preclinical models of brain cancers, as our lab has recently shown. These observations indicate that it is crucial to evaluate TAM abundance and dynamics in gliomas. Current techniques to quantify TAMs in patients rely mainly on histological staining of tumor biopsies. While informative, these techniques require an invasive procedure to harvest the tissue sample and typically only result in a snapshot of a small region at a single point in time. Fluorine isotope 19 MRI (19F MRI) has been shown to be a powerful tool to non-invasively and longitudinally monitor myeloid cells in other pathological conditions by injecting perfluorocarbon-containing nanoparticles (PFC-NP). In this study, we demonstrated the feasibility and power of 19F MRI in preclinical glioma models and brain metastasis models and showed that the major cellular source of 19F signal consists of TAMs. Moreover, PFC-NP accumulation occurred predominantly in proximity to dysmorphic vessels, thereby enabling the identification of a TAM subpopulation with a specific oxidative metabolism. We also evaluated this imaging modality in the context of irradiation (IR) treatment and found that the 19F signal enables the tracking of TAM dynamics over time following IR. Moreover, multispectral 19F MRI with two different PFC-NP allowed us to identify spatially- and temporally-distinct TAM niches in IR-recurrent tumors. Together, we have been able to image TAMs non-invasively and longitudinally with a powerful integrated cellular, spatial and temporal resolution, while revealing new biological insights into the many functions of TAMs, including in disease recurrence.

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Endothelial Rbpj is essential for the education of tumor-associated macrophages

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