Tumor-specific activation of folate receptor beta and its use in reprogramming the tumor microenvironment
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236443 | GEO | 2024/02/28
REPOSITORIES: GEO
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Project description:Macrophages and monocytes are essential components of the immune system that distinguish themselves from all other cells in the body by expressing a beta isoform of the folate receptor (FRβ). Because FRβ does not bind folate until the macrophage/monocyte is exposed to immunosuppressive cytokines, the question naturally arose whether FRβ might perform an immune-related function. We report here that FRβ knockout mice display autoimmune symptoms that can include alopecia, enlarged spleens, and dermatitis. We further show that bone marrow-derived macrophages from KO mice exhibit strong upregulation of pro-inflammatory genes and downregulation of anti-inflammatory genes. Exogenous inflammatory stimuli are also more intense in FRβ KO mice, and syngeneic tumors (TRAMP C2, MC38) grow much slower in FRβ-depleted mice. Analysis of these tumors further reveals that CD69+ T-cell populations are increased while PD1+ T-cells, PD-L1+ TAMs and PD-L1+ MDSCs are decreased in the malignant lesions. Because FRβ deletion or blockade of FRβ with a monoclonal antibody impairs a macrophages' ability to suppress T-cell activation, and since FRβ expression correlates inversely with human cancer patient survival, we conclude that FRβ performs a checkpoint function specifically in macrophages and MDSCs.
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Project description:Tumor-specific activation of folate receptor beta and its use in reprogramming the tumor microenvironment
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2012-03-29 | E-GEOD-35398 | biostudies-arrayexpress
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.
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