该研究组利用机械力来设计一种弱反应性T细胞受体（TCR），特异性针对非突变肿瘤相关抗原（TAA），前列腺酸性磷酸酶（PAP）。研究团队发现了一个捕获结合“热点”，其突变通过增加TCR-pMHC（肽-主要组织相容性复合体）结合寿命而增强T细胞活性，同时保持生理亲和力和抗原精细特异性。表达这些工程TCRs的T细胞在肿瘤、效应表型和肿瘤消除中表现出极大的优越性。晶体结构和分子动力学模拟表明，捕获键热点上的单个氨基酸突变启动了TCR-pMHC界面上通过水重组进行肽相互作用的TCR。Catch-bond工程是一种可行的基于生物物理的策略，可以将耐受的抗肿瘤T细胞转化为有效的TCR-T细胞治疗杀手。
据了解，T细胞对肿瘤自身抗原的反应通常较弱，这是中心耐受的主题，限制了它们消除肿瘤的能力。
附：英文原文
Title: Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering
Author: 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
Issue&Volume: 2026-03-19
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.
DOI: adx3162
Source: https://www.science.org/doi/10.1126/science.adx3162