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Preclinical evaluation of the efficacy of anti-human SIRPα antibody for cancer immunotherapy using the MITRG humanized mouse model

ABSTRACT: Tumor-associated macrophages (TAMs) represent abundantly in the tumor microenvironment (TME) and are thought to be novel targets for cancer immunotherapy. To elucidate the antitumor effects of therapeutics targeting human TAMs in vivo, we have here established a preclinical tumor xenograft model using immunodeficient mice expressing multiple human cytokines (MITRG mice) and examined the anti-tumor effect of anti–human SIRPα antibodies SE12C3, which inhibit the interaction of CD47 on tumor cells and enhance Fcγ receptor-mediated phagocytosis of tumor cells by human macrophages. Humanized immune system (HIS)–MITRG mice particularly facilitate human macrophage differentiation following transplantation of human CD34+ hematopoietic stem and progenitor cells. HIS–MITRG mice promoted the growth of both cell line– and patient–derived B cell lymphoma and infiltration of human TAMs into the tumor. Treatment of rituximab with SE12C3 markedly inhibited B–cell lymphoma growth in HIS-MITRG mice. The inhibition of B–cell lymphoma growth depended on human macrophages and was attributable to the promotion of rituximab–mediated lymphoma cell phagocytosis by human macrophages. In addition, the treatment of rituximab with SE12C3 induced reprogramming of human TAMs towards the pro-inflammatory phenotype in the TME. Furthermore, we demonstrated that the treatment of rituximab with SE12C3 significantly inhibited diffuse large B–cell lymphoma patient–derived tumor growth in HIS–MITRG mice. Together, HIS–MITRG mice provide an excellent mouse model for in vivo preclinical evaluation of the anti-tumor effect of therapeutics targeting human TAMs in the TME, such as anti–human SIRPα antibodies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239693 | GEO | 2023/09/30

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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Preclinical evaluation of the efficacy of anti-human SIRPα antibody for cancer immunotherapy using the MITRG humanized mouse model

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