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S100A4 blockage alleviates agonistic anti-CD137 antibody-induced liver pathology without disruption of antitumor
Jinhua Zhang1, Kun Song1,2, Jun Wang3
1Key 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.
Abstract:
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.
Insights
Anti-CD137 antibody therapy causes liver toxicity via S100A4+ macrophages. Targeting S100A4 reduces liver damage without compromising anti-tumor immune responses, offering a new immunotherapy strategy.
Area of Science:
- Immunology
- Oncology
- Hepatology
Background:
- Agonistic anti-CD137 antibodies show promise in cancer immunotherapy.
- Liver-related autoimmune toxicities limit the clinical application of anti-CD137 antibodies.
Purpose of the Study:
- To elucidate the mechanism underlying anti-CD137 antibody-induced liver toxicity.
- To identify potential therapeutic targets to mitigate these side effects.
Main Methods:
- Treatment of mice with anti-CD137 monoclonal antibody (mAb).
- Analysis of immune cell infiltration in the liver, including S100A4+ macrophages and CD8+ T cells.
- Assessment of inflammatory cytokine profiles and T cell survival pathways (Akt pathway).
- Evaluation of a S100A4 neutralizing mAb for its therapeutic potential.
Main Results:
- Anti-CD137 mAb treatment led to significant infiltration of S100A4+ macrophages in the liver.
- Depletion of S100A4+ cells or S100A4 deficiency reduced inflammatory cytokines and pathogenic CD8+ T cells.
- Soluble S100A4 activated the Akt pathway, prolonging CD8+ T cell survival.
- A S100A4 neutralizing mAb alleviated liver toxicity without affecting anti-tumor immunity.
Conclusions:
- S100A4+ macrophages are key mediators of liver pathology induced by anti-CD137 antibodies.
- Targeting S100A4 offers a promising strategy for combination immunotherapy to enhance anti-tumor efficacy while minimizing liver side effects.
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