2026-03-20 カリフォルニア大学ロサンゼルス校（UCLA）
＜関連情報＞
- https://newsroom.ucla.edu/releases/scientists-turbocharge-immune-cells-to-attack-prostate-cancer
- https://www.science.org/doi/10.1126/science.adx3162
キャッチボンドエンジニアリングによる腫瘍自己抗原に対するT細胞寛容の克服 Overcoming T cell tolerance to tumor self-antigens through catch-bond engineering
Xiaojing Chen, Zhiyuan Mao, E. Motunrayo Kolawole, Margherita Persechino, […] , and K. Christopher Garcia
Science Published:19 Mar 2026
DOI:https://doi.org/10.1126/science.adx3162
Editor’s summary
T cell therapies that target tumor-associated antigens represent a promising avenue to treat cancer. However, humans develop a natural protective immune tolerance to self-antigens that limits the ability of T cells to destroy tumors. Chen et al. tested a strategy known as catch-bond engineering to overcome immune tolerance. By substituting one or two amino acids to introduce catch bonds, the researchers were able to convert a weakly reactive T cell receptor (TCR) to a more potent tumor killer while maintaining the specificity for prostate cancer antigens. Structural analysis showed remodeling of the bonding pattern between the TCR and the tumor antigen. The ability to transform weak TCR-tumor antigen interactions may help overcome tolerance and improve cancer killing. —Priscilla N. Kelly
Structured Abstract
INTRODUCTION
Tumor-associated antigens (TAAs) are a class of targets without underlying mutations that are expressed in both benign and malignant tissues and shared across broad patient populations. TAAs represent promising candidates for T cell–mediated cancer immunotherapy, but central immune tolerance often eliminates T cell clones with high potency for such antigens. Naturally occurring T cell receptors (TCRs) that escape negative selection may exhibit limited efficacy, despite their ability to specifically recognize TAA-derived epitopes presented by major histocompatibility complexes (MHCs). Prostatic acid phosphatase (PAP) is a classic TAA, abundantly expressed only in benign and malignant prostate tissues. Recently identified PAP-specific TCRs from healthy donor peripheral blood exhibit limited cytotoxicity. Engineering strategies that enhance TCR-mediated cytotoxicity without compromising antigen specificity are needed to overcome central tolerance and advance TCR–T cell–based immunotherapies.
RATIONALE
Catch bonds are specialized interactions between TCRs and peptide-MHCs that increase bond lifetimes under mechanical force, extending the dwell time of the complex and augmenting signaling. Catch bonds are activated through TCR contact with antigen-presenting cells that takes place under shear force. By prolonging the interaction between T cells and cancer cells, catch bonds can enhance T cell potency while maintaining physiologically low TCR-MHC affinity and fast off-rates. We hypothesize that introducing catch bonds can convert weak, naturally occurring PAP-specific TCRs into potent and selective therapeutic candidates with minimal sequence modifications, while reducing the possibility of off-target cross-reactivity, as has been seen in affinity-matured TCR–T cells. To evaluate this, a rapid positional scanning approach was developed to identify potential sites for catch-bond engineering.
RESULTS
We established a new pipeline, called “TCR turbocharging,” to rescreen for and introduce catch-bond “hotspots” into TCRs without requiring prior structural information. This strategy was applied to a natural, PAP-reactive, HLA-A*02:01–restricted TCR (TCR156). Catch-bond hotspots were identified within the complementarity-determining region 1 (CDR1) of the TCRα chain. Multiple TCR156 variants with enhanced catch-bond formation were generated, all maintaining physiological TCR-MHC binding affinities (1 to 100 μM). Functional assays and biomembrane force probe measurements demonstrated a positive correlation between TCR-pMHC bond strength and TCR cytotoxic potency. Two candidate TCRs with the longest bond lifetimes—bearing one (S32Mα) or two (S30E32Qα) amino acid substitutions—exhibited significantly enhanced cytotoxicity both in vitro and in vivo. Crystal structures of the wild-type and engineered TCR156 variants revealed minimal structural perturbation after catch bond introduction. Molecular dynamics simulation and yeast MHC library screening suggest that the methionine mutation on the TCR chain indirectly induces an additional interaction between the PAP peptide and the TCR, which increased the specificity of the TCR. Yeast-display MHC library screening also confirmed that catch-bond engineering did not increase off-target reactivity.
CONCLUSION
The TCR turbocharging pipeline successfully enhanced the function of a naturally occurring, weak PAP-specific TCR, producing candidates with strong in vitro and in vivo cytotoxicity. Although a clinical path is envisioned, further preclinical evaluation is needed. This strategy holds promise for broad application to other TAAs, potentially expanding the utility of TCR–T cell immunotherapies and overcoming the limitations imposed by central immune tolerance.
Catch-bond–engineered TCRs exhibit improved antitumor potency.
(Left) Catch-bond hotspots were identified in a prostate antigen-specific T cell receptor interacting with the HLA-A2-PAP complex. Substitution of (top middle) the wild-type serine residue in the TCR with (bottom middle) methionine enhanced bond lifetime and resulted in (right) dramatically enhanced tumor elimination in tumor-bearing mice.
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.
