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Blockade of complement C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8+ T cell activity

ABSTRACT: Macrophages play a crucial role in shaping the immune state within tumor microenvironment (TME) and are often influenced by tumors to hinder antitumor immunity. However, the underlying mechanisms are still elusive. Here, we observed abnormal expression of complement 5a receptor (C5aR) in human ovarian cancer (OC), and identified high levels of C5aR expression on tumor-associated macrophages (TAMs), which led to the polarization of TAMs towards an immunosuppressive phenotype. C5aR knockout or inhibitor treatment restored TAM antitumor response and attenuated tumor progression. Mechanistically, C5aR deficiency reprogrammed macrophages from a protumor state to an antitumor state, associating with the upregulation of immune response and stimulation pathways, which in turn resulted in the enhanced antitumor response of cytotoxic T cells in a manner dependent on chemokine (C-X-C motif) ligand 9 (CXCL9). The pharmacological inhibition of C5aR also improved the efficacy of immune checkpoint blockade therapy. In patients, C5aR expression associated with CXCL9 production and infiltration of CD8+ T cells, and high C5aR level predicted poor clinical outcomes and worse benefits from anti-PD-1 therapy. Thus, our study sheds light on the mechanisms underlying the modulation of TAM antitumor immune response by the C5a-C5aR axis and highlights the potential of targeting C5aR for clinical applications.

ORGANISM(S): Mus musculus

PROVIDER: GSE243210 | GEO | 2023/09/19

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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Blockade of complement C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8+ T cell activity

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