PT - JOURNAL ARTICLE AU - Marc Pfefferlé AU - Irina L Dubach AU - Raphael M Buzzi AU - Elena Dürst AU - Nadja Schulthess-Lutz AU - Livio Baselgia AU - Kerstin Hansen AU - Larissa Imhof AU - Sandra Koernig AU - Didier Le Roy AU - Thierry Roger AU - Rok Humar AU - Dominik J Schaer AU - Florence Vallelian TI - Antibody-induced erythrophagocyte reprogramming of Kupffer cells prevents anti-CD40 cancer immunotherapy-associated liver toxicity AID - 10.1136/jitc-2022-005718 DP - 2023 Jan 01 TA - Journal for ImmunoTherapy of Cancer PG - e005718 VI - 11 IP - 1 4099 - http://jitc.bmj.com/content/11/1/e005718.short 4100 - http://jitc.bmj.com/content/11/1/e005718.full SO - J Immunother Cancer2023 Jan 01; 11 AB - 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.Data are available in a public, open access repository. Data are available on reasonable request.