Immune stimulatory monoclonal antibodies are currently evaluated as antitumor agents in clinical trials. Although overall toxicity appears to be moderate, liver toxicities have been reported and are not completely understood. Therefore, we decided to study the effect of systemic CD40 antibody treatment on the liver immune microenvironment. Agonistic CD40 antibody or isotype control was injected intraperitoneally into naïve and tumor-bearing mice. Liver enzymes, histologies and immune infiltrates were analyzed after antibody administration. The effect of agonistic CD40 administration was evaluated using bone marrow chimeras and genetically modified mouse strains Cd40-/- and Nox2-/-. Mouse and human tumor-induced myeloid suppressive cells were cultured to address changes in their immune function upon CD40 ligation. Agonistic CD40 antibody caused liver damage within 24 hours after injection in two unrelated tumor models and mice strains. Using bone marrow chimeras we could demonstrate that CD40 antibody-induced hepatitis in tumor-bearing mice was dependent on the presence of CD40+ immune cells. Agonistic CD40 ligation-dependent liver damage was induced by the generation of reactive oxygen species. Furthermore, agonistic CD40 antibody resulted in increased CD80 and CD40 positive liver CD11b+Gr-1+ immature myeloid cells. CD40 ligation on tumor-induced hepatic myeloid cells or CD14+HLA-DRlow PBMC from cancer patients reduced their immune suppressor function. Collectively, agonistic CD40 antibody activates the tumor-induced liver myeloid suppressive compartment, enhancing acute inflammation and thus liver damage. Our data in murine and human myeloid suppressive cells point towards a pivotal role for CD40 as a key molecule in modulating myeloid suppressive cell plasticity.
Citation Format: Jose Medina-Echeverz, Chi Ma, Tobias Eggert, Tim F. Greten. Systemic agonistic anti-CD40 treatment of tumor bearing mice modulates hepatic myeloid suppressive cells and causes immune-mediated liver damage. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A04.
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