S100A4 blockage alleviates agonistic anti-CD137 antibody-induced liver pathology without disruption of antitumor immunity

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.