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Tumoral Interferon Beta Induces an Immune-Stimulatory Phenotype in Tumor-Associated Macrophages in Melanoma Brain Metastases

ABSTRACT: Type I interferons (IFNs) are immune-stimulatory cytokines involved in antiviral and antitumor immune responses. They enhance the efficacy of immunogenic anticancer therapies by activating both innate and adaptive intratumoral immune cell populations. Macrophages are one of the most abundant innate immune cells in the immune microenvironment of melanoma brain metastases (MBMs) and can exert potent immune-suppressive functions. Here, we investigate the potential of tumoral type I IFNs to re-polarize tumor-associated macrophages (TAMs) in a murine melanoma mouse model. We describe a pro-inflammatory and M1-like TAM phenotype induced by tumoral IFNβ and identify a myeloid type I interferon-response signature associated with a high M1/M2 TAM ratio and an increased overall survival in previously irradiated patients with MBMs. We provide evidence that tumoral IFNβ supports an effective antitumor immune response by re-educating immune-regulatory TAMs. These findings uncover type I interferon-dependent therapies as a potential macrophage-targeting therapeutic approach and provide a rationale for combining radiotherapy with concomitant immunotherapy to improve treatment response in patients with MBM.

ORGANISM(S): Mus musculus

PROVIDER: GSE271267 | GEO | 2024/08/07

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.

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Tumoral Interferon Beta Induces an Immune-Stimulatory Phenotype in Tumor-Associated Macrophages in Melanoma Brain Metastases

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