Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering

TL;DR

Researchers engineered T cells to better recognize tumor antigens by modifying TCR bonds, improving their ability to fight cancer.

Contribution

A novel biophysical strategy using catch-bond engineering to enhance TCR function against tumor self-antigens.

Findings

Engineered TCRs showed increased TCR-pMHC bond lifetime and T cell activity.

Modified T cells exhibited superior tumor expansion and tumor elimination.

Structural analysis revealed how a single mutation improves TCR-peptide interaction.

Abstract

T cells are often weakly responsive to tumor self-antigens because of central tolerance, constraining their ability to eliminate tumors. We exploited mechanical force to engineer a weakly reactive TCR specific for a non-mutated tumor associated antigen (TAA), Prostatic Acid Phosphatase (PAP). We identified a catch-bonding “hotspot” whose mutation enhanced T cell activity by increasing TCR-pMHC bond lifetime, whilst preserving physiological affinities and antigen fine-specificities. T cells expressing these engineered TCRs showed vastly superior expansion in the tumor, effector phenotypes and tumor elimination. Crystal structures and molecular dynamics simulations reveal a single amino acid mutation at the catch bond hotspot primes the TCR for peptide interaction through water reorganization at the TCR-pMHC interface. Catch bond engineering is a viable biophysically-based strategy for transforming tolerized anti-tumor T cells into potent TCR-T killers.

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