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Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity

BACKGROUND: Agonistic 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 pro...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809320/
https://www.ncbi.nlm.nih.gov/pubmed/36593065
http://dx.doi.org/10.1136/jitc-2022-005718
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author 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
author_facet 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
author_sort Pfefferlé, Marc
collection PubMed
description BACKGROUND: Agonistic 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. METHODS: We 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. RESULTS: We 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 Hmox(high)/Marco(high)/MHCII(low) anti-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. CONCLUSIONS: Our study offers a targeted approach to uncouple CD40-augmented antitumor immunity in peripheral tissues from harmful inflammatoxicity in the liver.
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spelling pubmed-98093202023-01-04 Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity 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 J Immunother Cancer Immune Cell Therapies and Immune Cell Engineering BACKGROUND: Agonistic 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. METHODS: We 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. RESULTS: We 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 Hmox(high)/Marco(high)/MHCII(low) anti-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. CONCLUSIONS: Our study offers a targeted approach to uncouple CD40-augmented antitumor immunity in peripheral tissues from harmful inflammatoxicity in the liver. BMJ Publishing Group 2023-01-02 /pmc/articles/PMC9809320/ /pubmed/36593065 http://dx.doi.org/10.1136/jitc-2022-005718 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Immune Cell Therapies and Immune Cell Engineering
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
Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity
title Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity
title_full Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity
title_fullStr Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity
title_full_unstemmed Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity
title_short Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity
title_sort antibody-induced erythrophagocyte reprogramming of kupffer cells prevents anti-cd40 cancer immunotherapy-associated liver toxicity
topic Immune Cell Therapies and Immune Cell Engineering
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9809320/
https://www.ncbi.nlm.nih.gov/pubmed/36593065
http://dx.doi.org/10.1136/jitc-2022-005718
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