Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity
| Autor: | Pfefferlé, Marc, Dubach, Irina L, Buzzi, Raphael M, Dürst, Elena, Schulthess-Lutz, Nadja, Baselgia, Livio, Hansen, Kerstin, Imhof, Larissa, Koernig, Sandra, Le Roy, Didier, Roger, Thierry, Humar, Rok, Schaer, Dominik J, Vallelian, Florence |
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| Přispěvatelé: | University of Zurich |
| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
Pharmacology
2403 Immunology Cancer Research Immunology Mice Animals Kupffer Cells/metabolism Antibodies Monoclonal/therapeutic use Antineoplastic Agents/therapeutic use Immunotherapy/methods Liver Neoplasms Immunity Innate Immunotherapy Macrophages 610 Medicine & health 3004 Pharmacology Oncology 1313 Molecular Medicine 2723 Immunology and Allergy Molecular Medicine Immunology and Allergy 2730 Oncology 1306 Cancer Research 10029 Clinic and Policlinic for Internal Medicine |
| Zdroj: | Journal for immunotherapy of cancer, vol. 11, no. 1, pp. e005718 |
| Popis: | BackgroundAgonistic anti-CD40 monoclonal antibodies (mAbs) have emerged as promising immunotherapeutic compounds with impressive antitumor effects in mouse models. However, preclinical and clinical studies faced dose-limiting toxicities mediated by necroinflammatory liver disease. An effective prophylactic treatment for liver immune-related adverse events that does not suppress specific antitumor immunity remains to be found.MethodsWe used different mouse models and time-resolved single-cell RNA-sequencing to characterize the pathogenesis of anti-CD40 mAb induced liver toxicity. Subsequently, we developed an antibody-based treatment protocol to selectively target red blood cells (RBCs) for erythrophagocytosis in the liver, inducing an anti-inflammatory liver macrophage reprogramming.ResultsWe discovered that CD40 signaling in Clec4f+Kupffer cells is the non-redundant trigger of anti-CD40 mAb-induced liver toxicity. Taking advantage of the highly specific functionality of liver macrophages to clear antibody-tagged RBCs from the blood, we hypothesized that controlled erythrophagocytosis and the linked anti-inflammatory signaling by the endogenous metabolite heme could be exploited to reprogram liver macrophages selectively. Repeated low-dose administration of a recombinant murine Ter119 antibody directed RBCs for selective phagocytosis in the liver and skewed the phenotype of liver macrophages into a Hmoxhigh/Marcohigh/MHCIIlowanti-inflammatory phenotype. This unique mode of action prevented necroinflammatory liver disease following high-dose administration of anti-CD40 mAbs. In contrast, extrahepatic inflammation, antigen-specific immunity, and antitumor activity remained unaffected in Ter119 treated animals.ConclusionsOur study offers a targeted approach to uncouple CD40-augmented antitumor immunity in peripheral tissues from harmful inflammatoxicity in the liver. |
| Databáze: | OpenAIRE |
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