1. Activation of 4-1BB on Liver Myeloid Cells Triggers Hepatitis via an Interleukin-27-Dependent Pathway.
- Author
-
Bartkowiak T, Jaiswal AR, Ager CR, Chin R, Chen CH, Budhani P, Ai M, Reilley MJ, Sebastian MM, Hong DS, and Curran MA
- Subjects
- Animals, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, CTLA-4 Antigen antagonists & inhibitors, CTLA-4 Antigen immunology, Cell Line, Tumor transplantation, Chemical and Drug Induced Liver Injury etiology, Chemical and Drug Induced Liver Injury pathology, Drug Evaluation, Preclinical, Humans, Interleukins immunology, Liver cytology, Liver drug effects, Liver immunology, Liver pathology, Male, Melanoma, Experimental drug therapy, Melanoma, Experimental immunology, Melanoma, Experimental pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells drug effects, Myeloid Cells immunology, Myeloid Cells metabolism, Receptors, CCR2 antagonists & inhibitors, Receptors, CCR2 immunology, Signal Transduction drug effects, Signal Transduction immunology, Skin Neoplasms drug therapy, Skin Neoplasms immunology, Skin Neoplasms pathology, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Chemical and Drug Induced Liver Injury immunology, Interleukins metabolism, Tumor Necrosis Factor Receptor Superfamily, Member 9 agonists
- 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
+ regulatory T cells limit liver damage, and their removal dramatically exacerbates 4-1BB agonist-induced hepatitis. Coadministration of CTLA-4 blockade ameliorates transaminase elevation, whereas PD-1 blockade exacerbates it. Loss of the chemokine receptor CCR2 blocks 4-1BB agonist hepatitis without diminishing tumor-specific immunity against B16 melanoma. Conclusions: 4-1BB agonist antibodies trigger hepatitis via activation and expansion of interleukin-27-producing liver Kupffer cells and monocytes. Coadministration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity. Clin Cancer Res; 24(5); 1138-51. ©2018 AACR ., (©2018 American Association for Cancer Research.)- Published
- 2018
- Full Text
- View/download PDF