Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27-Dependent Pathway

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Todd BartkowiakMichael A Curran

Abstract

Purpose: Agonist antibodies targeting the T-cell costimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across preclinical cancer models. In the clinic, however, development of these agents has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist-driven tumor immunity from hepatotoxicity.Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immunocompetent mice, with or without coadministration of checkpoint blockade, via (i) measurement of serum transaminase levels, (ii) imaging of liver immune infiltrates, and (iii) qualitative and quantitative assessment of liver myeloid and T cells via flow cytometry. Knockout mice were used to clarify the contribution of specific cell subsets, cytokines, and chemokines.Results: We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage, triggering transaminase elevation. FoxP3+ regu...Continue Reading

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Feb 14, 2020·American Journal of Hematology·John TimmermanRonald Levy
Aug 23, 2018·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Bushra Husain, Diego Ellerman
Jul 3, 2020·ESMO Open·Iñaki EtxeberriaIgnacio Melero
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Jun 27, 2021·Proceedings of the National Academy of Sciences of the United States of America·Iñaki EtxeberriaIgnacio Melero
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Oct 1, 2019·Journal of Autoimmunity·Chuan HuangZhe-Xiong Lian

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