LAUSR

Liver-related autoimmune toxicities triggered by anti-CD137 agonist antibodies have greatly limited their use in clinic 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 monoclonal antibody selectively alleviated liver abnormalities but did not affect the anti-tumor immunity induced by anti-CD137 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 anti-tumor immunity with minimal side effects. Note: This abstract was not presented at the meeting. Citation Format: Jinhua Zhang, Kun Song, Zhihai Qin. S100A4 blockage alleviates agonistic anti-CD137 antibody induced liver pathology without disruption of anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1616. doi:10.1158/1538-7445.AM2017-1616