摘要:4-1BB在肝髓细胞上的激活通过白细胞介素-27依赖途径触发肝炎

A. Jaiswal, T. Bartkowiak, C. Ager, Renee L Chin, Chao-Hsien Chen, Pratha Budhani, Midan Ai, M. Reilley, Manu Sebastian, D. Hong, M. Curran
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引用次数: 0

摘要

目的:靶向T细胞共刺激受体4-1BB (CD137)的激动剂抗体是多种癌症临床前模型中最有效的免疫治疗药物之一。然而,在临床上,这些药物的开发一直受到剂量限制性肝毒性的阻碍。缺乏对这种毒性机制的了解限制了将4-1BB激动剂驱动的抗肿瘤免疫从肝毒性中分离出来的可能性。实验设计:通过测量血清转氨酶水平、肝脏免疫浸润成像以及流式细胞术对肝髓细胞和T细胞进行定性和定量评估,在免疫正常的小鼠中研究了4-1BB激动剂抗体诱导肝毒性的能力,无论是否联合使用检查点阻断。用敲除小鼠来阐明特定细胞亚群、细胞因子和趋化因子的作用。结果:我们发现4-1BB对肝髓细胞的激活是引发肝炎的必要条件。一旦被激活,这些细胞就会产生白细胞介素-27,这是肝毒性所必需的。CD8 T细胞浸润肝脏,响应骨髓活化,介导组织损伤,引发转氨酶升高。FoxP3+调节性T细胞限制肝损伤,其去除可显著加重4-1BB激动性肝炎。CTLA-4阻断可改善转氨酶升高,而PD-1阻断可加重转氨酶升高。趋化因子受体CCR2的缺失可阻断4-1BB激动剂肝炎,但不降低针对B16黑色素瘤的肿瘤特异性免疫。结论:4-1BB激动剂抗体通过激活髓细胞产生白细胞介素-27触发肝炎。同时使用CTLA-4和/或CCR2阻断剂可以减少肝炎,但产生相同或更大的抗肿瘤免疫。引文格式:Ashvin R. Jaiswal, Todd Bartkowiak, Casey R. Ager, Renee Chin, Chao Hsien Chen, Pratha Budhani, Midan Ai, Matthew J. Reilley, Manu M. Sebastian, David Hong, Michael A. Curran肝髓细胞上4-1BB的激活通过白细胞介素-27依赖途径触发肝炎[摘要]。摘自:AACR肿瘤免疫学和免疫治疗特别会议论文集;2017年10月1-4日;波士顿,MA。费城(PA): AACR;癌症免疫学杂志,2018;6(9增刊):摘要nr A21。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Abstract A21: Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway
Purpose: Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across multiple preclinical models of cancer. In the clinic, however, development of these agents has been stymied by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven anti-tumor immunity from hepatotoxicity. Experimental Design: The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in immune competent mice, with or without co-administration of checkpoint blockade, via measurement of serum transaminase levels, through imaging of liver immune infiltrates, and via 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, which 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 hepatitis. Co-administration 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 of myeloid cells to produce Interleukin-27. Co-administration of CTLA-4 and/or CCR2 blockade may minimize hepatitis but yields equal or greater antitumor immunity. Citation Format: Ashvin R. Jaiswal, Todd Bartkowiak, Casey R. Ager, Renee Chin, Chao Hsien Chen, Pratha Budhani, Midan Ai, Matthew J. Reilley, Manu M. Sebastian, David Hong, Michael A. Curran. Activation of 4-1BB on liver myeloid cells triggers hepatitis via an interleukin-27 dependent pathway [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A21.
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