Zhang Jinhua, Song Kun, Wang Jun, Li Yanan, Liu Shuangqing, Dai Chengliang, Chen Lieping, Wang Shengdian, Qin Zhihai
Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Oncoimmunology. 2018 Jan 23;7(4):e1296996. doi: 10.1080/2162402X.2017.1296996. eCollection 2018.
Liver-related autoimmune toxicities triggered by agonistic anti-CD137 antibodies have greatly limited their use in clinical applications. Here, we found that anti-CD137 monoclonal antibody (mAb) treatment in mice induced the infiltration of a large number of S100A4 macrophages into the liver. Depletion of these cells or deficiency of S100A4 decreased inflammatory cytokine profiles and drastically reduced the number of liver pathogenic CD8 T cells. Mechanistically, soluble S100A4 directly activated the Akt pathway and specifically prolonged CD8 T cell survival. Interestingly, one S100A4 neutralizing mAb selectively alleviated liver abnormalities but did not affect the antitumor immunity induced by anti-CD137 mAb therapy. Thus, our study presents a novel molecular link to the liver pathology induced by an immune stimulatory antibody and proposes that combinational immunotherapies targeting those pathways could potentially elicit optimal antitumor immunity with minimal side effects.
激动性抗CD137抗体引发的肝脏相关自身免疫毒性极大地限制了它们在临床应用中的使用。在此，我们发现小鼠接受抗CD137单克隆抗体（mAb）治疗会诱导大量S100A4巨噬细胞浸润到肝脏中。这些细胞的清除或S100A4的缺乏会降低炎性细胞因子水平，并大幅减少肝脏致病性CD8 T细胞的数量。从机制上讲，可溶性S100A4直接激活Akt通路，并特异性地延长CD8 T细胞的存活时间。有趣的是，一种S100A4中和mAb可选择性减轻肝脏异常，但不影响抗CD137 mAb治疗诱导的抗肿瘤免疫。因此，我们的研究揭示了免疫刺激抗体诱导肝脏病理的一种新的分子联系，并提出针对这些通路的联合免疫疗法可能以最小的副作用引发最佳的抗肿瘤免疫。
