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Effects of Cryo-thermal therapy on gene expression in neutrophils and monocytes

ABSTRACT: The characteristics of the tumor immunosuppressive microenvironment represent a major challenge limiting the efficacy of immunotherapy. Our previous results suggested that cryo-thermal therapy (CTT), a tumor ablation system developed in our laboratory, could promote macrophage M1-type polarization and full maturation of DCs to remodel the immunosuppressive environment. However, it is not clear which cells respond promptly to CTT. CTT can cause extensive cell death and the release of danger-associated molecular patterns (DAMPs) and antigens. Neutrophils are the first white blood cells recruited to sites of damage and acute inflammation. We therefore hypothesized that neutrophils were the initial cells to respond to CTT and were involved in the subsequent establishment of antitumor immunity. We found that CTT led to a rapid and strong proinflammatory neutrophil response, which was essential for the long-term survival of mice. In vivo neutrophil depletion and in vitro coculture experiments demonstrated that CTT-induced neutrophils promoted the differentiation of monocytes toward to mature antigen presenting cells and further upregulated the expression of IFN-γ and cytotoxic molecules in T and NK cells in a CD86-dependent manner. These results reveal the important role of neutrophil-monocyte interactions for the development of anti-tumor immunity and highlight that CTT could be used as an immunotherapy for targeting neutrophils and monocytes to enhance antitumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE259010 | GEO | 2024/03/02

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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Effects of Cryo-thermal therapy on gene expression in neutrophils and monocytes

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