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
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 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.