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HDAC2-SP1 orchestrated M2-like macrophage phenotype drives lung cancer growth – novel intervention strategy

ABSTRACT: Tumor-associated macrophages (TAMs), including anti-tumor M1-like TAMs and pro-tumor M2-like TAMs, are transcriptionally dynamic innate immune cells with diverse roles in lung cancer development. Epigenetic regulators are key controllers of macrophage fate in the spatially heterogeneous tumor microenvironment. Here, we demonstrate that the spatial proximity of histone deacetylase 2 (HDAC2) – overexpressing M2-like macrophages to tumor cells significantly correlates with poor overall survival of lung cancer patients. Suppression of HDAC2 in TAMs altered macrophage polarization, migration, and associated signaling pathways related to interleukin, chemokine, cytokine, and T cell activation. In various co-culture systems of TAMs and cancer cells, suppressing HDAC2 in TAMs results in reduced proliferation and migration and increased apoptosis of cancer cell lines and primary lung cancer cells, as well as attenuated endothelial cell tube length. HDAC2 regulates the pro-tumor macrophage phenotype via acetylation of histone H3 and transcription factor SP1. Myeloidcell–specificc deletion of Hdac2 (Hdac2f/fLysmCre) and pharmacological inhibition of class I HDACs in four different murine lung cancer models (intravenous, intratracheal, tumor relapse, and KrasLA2-driven) induced M2-like to M1-like macrophage phenotypic switching, altered infiltration of CD4 and CD8 T cells and retarded tumor growth and tumor microenvironmental angiogenesis. ThuTAM-specific HDAC2 expression may provide a novel strategy for lung cancer stratification and therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE227560 | GEO | 2023/05/16

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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HDAC2-SP1 orchestrated M2-like macrophage phenotype drives lung cancer growth – novel intervention strategy

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