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Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity [Multiplexed_CD40]

ABSTRACT: Agonistic CD40 monoclonal antibodies have emerged as promising immunotherapeutic compounds with impressive anti-tumoral effects. However, one of the main limitations of their use in patients is the severe liver necro-hepatitis they can induce. Up to this point, no effective treatment for anti-CD40 liver toxicity that does not hinder anti-tumor efficacy has been found. In the present study , we show that anti-CD40 liver toxicity is dependent on liver macrophages and recruitment of monocytes and neutrophils. We specifically reprogrammed the phenotype of liver macrophages to anti-inflammatory erythrophagocytes by using repeated injection of anti-erythrocyte murine Ter119 (mTer119) antibody. mTer119 administration induced phagocytosis of erythrocytes by liver macrophages and their transformation to Hmoxhigh/Marcohigh/MHC-IIlow erythrophagocytes. mTer119 treatment prevented anti-CD40 induced liver toxic side-effect, with significantly reduced elevation of plasma transaminases level and area of liver necrosis on histology, while preserving the anti-tumoral efficiency of anti-CD40. Our study offers a novel targeted therapeutic approach to treat immune-related liver adverse side effects of immunotherapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE202916 | GEO | 2022/11/09

REPOSITORIES: GEO

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Targeted erythrophagocyte reprogramming of Kupffer cells halts cancer immunotherapy associated liver toxicity [Ter119 experiment]

Project description:Agonistic CD40 monoclonal antibodies have emerged as promising immunotherapeutic compounds with impressive anti-tumoral effects. However, one of the main limitations of their use in patients is the severe liver necro-hepatitis they can induce. Up to this point, no effective treatment for anti-CD40 liver toxicity that does not hinder anti-tumor efficacy has been found. In the present study , we show that anti-CD40 liver toxicity is dependent on liver macrophages and recruitment of monocytes and neutrophils. We specifically reprogrammed the phenotype of liver macrophages to anti-inflammatory erythrophagocytes by using repeated injection of anti-erythrocyte murine Ter119 (mTer119) antibody. mTer119 administration induced phagocytosis of erythrocytes by liver macrophages and their transformation to Hmoxhigh/Marcohigh/MHC-IIlow erythrophagocytes. mTer119 treatment prevented anti-CD40 induced liver toxic side-effect, with significantly reduced elevation of plasma transaminases level and area of liver necrosis on histology, while preserving the anti-tumoral efficiency of anti-CD40. Our study offers a novel targeted therapeutic approach to treat immune-related liver adverse side effects of immunotherapies.

2022-11-09 | GSE202917 | GEO

Erythrophagocytosis drives anti-inflammatory programming of liver macrophages (Bulk RNA seq SPTA CD40 mac)

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Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy

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Cancer immunotherapy via synergistic co-activation of myeloid cells [scRNA-seq]

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