Generation of T cells with reduced off-target cross-reactivities by engineering co-signalling receptors
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Adoptive T cell therapy using T cells engineered with novel T cell receptors (TCRs) targeting tumor-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-to-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 any TCR.
One sentence summary
Switching the CD8 for the CD4 co-receptor in cytotoxic T cells reduces the functional cross-reactivity of T cells without modifying the TCR.
