Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering - PubMed
5 hours ago
- #biophysical engineering
- #T cell therapy
- #tumor antigens
- T cells often show weak responses to tumor self-antigens due to central tolerance, limiting their tumor elimination capability.
- Researchers engineered a weakly reactive T cell receptor (TCR) specific for prostatic acid phosphatase (PAP), a nonmutated tumor-associated antigen (TAA).
- A catch-bonding 'hotspot' was identified; its mutation enhanced T cell activity by increasing TCR-pMHC bond lifetime while maintaining physiological affinities and antigen specificity.
- T cells with engineered TCRs demonstrated superior tumor expansion, effector phenotypes, and tumor elimination.
- Structural and computational analyses revealed that a single amino acid mutation at the catch-bond hotspot reorganizes water at the TCR-pMHC interface, priming the TCR for peptide interaction.
- Catch-bond engineering presents a biophysical strategy to convert tolerized antitumor T cells into effective TCR-T cell therapy agents.