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<p>Adoptive T cell therapy using T cells engineered with novel T cell receptors (TCRs) targeting tumour-specific peptides is a promising immunotherapy. However, these TCR-T cells can cross-react with off-target peptides, leading to severe autoimmune toxicities. Current efforts focus on identifying TCRs with reduced cross-reactivity. Here we show that T cell cross-reactivity can be controlled by the co-signalling molecules CD5, CD8 and CD4, without modifying the TCR. We find the largest reduction in cytotoxic T cell cross-reactivity by knocking out CD8 and expressing CD4. Cytotoxic T cells engineered with a CD8→CD4 co-receptor switch show reduced cross-reactivity to random and positional scanning peptide libraries, as well as to self-peptides, while maintaining their on-target potency. Therefore, co-receptor switching generates super selective T cells that reduce the risk of lethal off-target cross-reactivity and offers a universal method to enhance the safety of T cell immunotherapies for potentially any TCR.</p>

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Generation of T cells with reduced off-target cross-reactivities by engineering co-signalling receptors

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月2日

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  • Jose Cabezas-Caballero,
  • Anna Huhn,
  • Mikhail A. Kutuzov,
  • Violaine Andre,
  • Alina Shomuradova,
  • Bas W. A. Peeters,
  • Geraldine M. Gillespie,
  • P. Anton van der Merwe,
  • Omer Dushek

摘要

Adoptive T cell therapy using T cells engineered with novel T cell receptors (TCRs) targeting tumour-specific peptides is a promising immunotherapy. However, these TCR-T cells can cross-react with off-target peptides, leading to severe autoimmune toxicities. Current efforts focus on identifying TCRs with reduced cross-reactivity. Here we show that T cell cross-reactivity can be controlled by the co-signalling molecules CD5, CD8 and CD4, without modifying the TCR. We find the largest reduction in cytotoxic T cell cross-reactivity by knocking out CD8 and expressing CD4. Cytotoxic T cells engineered with a CD8→CD4 co-receptor switch show reduced cross-reactivity to random and positional scanning peptide libraries, as well as to self-peptides, while maintaining their on-target potency. Therefore, co-receptor switching generates super selective T cells that reduce the risk of lethal off-target cross-reactivity and offers a universal method to enhance the safety of T cell immunotherapies for potentially any TCR.