To improve TCR-T cell specificity without altering the TCR, Cabezas-Caballero et al. explored the impact of TCR co-receptors on ligand discrimination. CD8 KO in NY-ESO-1 or MAGE-A3 TCR-T cells maintained responses against target peptides and reduced cross-reactivity. With an MHC-I-directed TCR, CD4+ T cells had improved ligand discrimination compared to CD8+ T cells, and CD4 knock-in had similar effects to CD8 KO. Dual CD8 KO + CD4 KI further reduced cytotoxic T cell reactivity against random peptides, single amino acid variants of a target peptide, or predicted cross-reactive peptides, without reducing on-target responses.
Contributed by Alex Najibi
ABSTRACT: 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.
Author Info: (1) Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. (2) Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. (3) Sir William Dunn School
Author Info: (1) Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. (2) Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. (3) Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. (4) Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. (5) Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. (6) Nuffield Department of Medicine, University of Oxford, Oxford, UK. (7) Nuffield Department of Medicine, University of Oxford, Oxford, UK. (8) Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. (9) Sir William Dunn School of Pathology, University of Oxford, Oxford, UK. omer.dushek@path.ox.ac.uk.
