Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering
- Xiaojing Chen
- Zhiyuan Mao
- E. Motunrayo Kolawole
- Margherita Persechino
- Kevin M. Jude
- Masato Ogishi
- Kelvin C. Mo
- Jami McLaughlin
- Donghui Cheng
- Xinyu Xiang
- Xinbo Yang
- Caitlin Gee
- Shiqin Liu
- Aerin Yang
- Matthias Obenaus
- Nan Wang
- Miyako Noguchi
- Tanya Stoyanova
- John K. Lee
- Zinaida Good
- Naomi R. Latorraca
- Brian D. Evavold
- Owen N. Witte
- K. Christopher Garcia
2026-03-19
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 T cell receptor (TCR) specific for a nonmutated tumor-associated antigen (TAA), prostatic acid phosphatase (PAP). We identified a catch-bonding “hotspot” whose mutation enhanced T cell activity by increasing TCR–pMHC (peptide–major histocompatibility complex) bond lifetime while 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 revealed 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 antitumor T cells into potent TCR–T cell therapy killers.