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Transcriptomic profiling of Bone Marrow Derived Macrophages (BMDM) treated with KN93 by RNA sequencing

ABSTRACT: Studies have revealed that TAMs can promote tumor immune escape, tumor growth, angiogenesis, and metastasis. Targeting TAMs to reset M2 towards the anti-tumor M1 phenotype is considered as a promising strategy in cancer immunotherapy. Interestingly, we found in the current investigation that the expression level of CAMKII mRNA in M2 was much higher than that in M1 . Based on this finding, the CAMKII specific inhibitor KN93 was used to explore the effect on bone marrow-derived macrophages. Strikingly, KN93 significantly increased the expression of CD86 (M1 marker) and reduced CD206 (M2 marker) expression in a concentration-dependent manner by the flow cytometry. To further verify whether KN93 could affect the polarization of BMDMs at the transcriptome level, we cultured BMDMs with KN93 (5 μM or 10 μM) or PBS for 24 h and analyzed the global transcriptional profile in cells through RNA sequencing. Compared with control cells, KN93-treated BMDMs expressed significantly higher levels of M1-related transcriptional factors, cytokines and other molecules and lower levels of M2-associated transcriptional factors, cytokines and other molecules. Conclusively, these results demonstrate that targeting CAMKII reprogramed M2 toward the M1 phenotype in vitro.

ORGANISM(S): Mus musculus

PROVIDER: GSE143552 | GEO | 2023/01/01

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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Transcriptomic profiling of Bone Marrow Derived Macrophages (BMDM) treated with KN93 by RNA sequencing

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