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 prop...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005718.full |
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| author | Florence Vallelian Marc Pfefferlé Irina L Dubach Raphael M Buzzi Elena Dürst Nadja Schulthess-Lutz Livio Baselgia Kerstin Hansen Larissa Imhof Sandra Koernig Didier Le Roy Thierry Roger Rok Humar Dominik J Schaer |
| author_facet | Florence Vallelian Marc Pfefferlé Irina L Dubach Raphael M Buzzi Elena Dürst Nadja Schulthess-Lutz Livio Baselgia Kerstin Hansen Larissa Imhof Sandra Koernig Didier Le Roy Thierry Roger Rok Humar Dominik J Schaer |
| author_sort | Florence Vallelian |
| collection | DOAJ |
| 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 Hmoxhigh/Marcohigh/MHCIIlow 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. |
| format | Article |
| id | doaj-art-e45a91d52e2f4d41a4e81a4dfbfec1fa |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-e45a91d52e2f4d41a4e81a4dfbfec1fa2025-01-29T10:25:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005718Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicityFlorence Vallelian0Marc Pfefferlé1Irina L Dubach2Raphael M Buzzi3Elena Dürst4Nadja Schulthess-Lutz5Livio Baselgia6Kerstin Hansen7Larissa Imhof8Sandra Koernig9Didier Le Roy10Thierry Roger11Rok Humar12Dominik J Schaer13University of Zurich, Zurich, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandCSL Ltd., Research, Bio21 Institute, Parkville, Victoria, AustraliaUniversity of Lausanne, Lausanne, SwitzerlandUniversity of Lausanne, Lausanne, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandUniversity of Zurich, Zurich, SwitzerlandBackground 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 Hmoxhigh/Marcohigh/MHCIIlow 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.https://jitc.bmj.com/content/11/1/e005718.full |
| spellingShingle | Florence Vallelian Marc Pfefferlé Irina L Dubach Raphael M Buzzi Elena Dürst Nadja Schulthess-Lutz Livio Baselgia Kerstin Hansen Larissa Imhof Sandra Koernig Didier Le Roy Thierry Roger Rok Humar Dominik J Schaer Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity Journal for ImmunoTherapy of Cancer |
| 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 |
| url | https://jitc.bmj.com/content/11/1/e005718.full |
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