Adoptive T cell immunotherapies, including engineered T cell receptor (eTCR) and chimeric antigen receptor (CAR) T cell immunotherapies, have shown efficacy in treating a subset of hematologic malignancies, exhibit promise in solid tumors, and have many other potential applications, such as in fibrosis, autoimmunity, and regenerative medicine. While immunoengineering has focused on designing biomaterials to present biochemical cues to manipulate T cells ex vivo and in vivo, mechanical cues that regulate their biology have been largely underappreciated. This review highlights the contributions of mechanical force to several receptor–ligand interactions critical to T cell function, with central focus on the TCR–peptide-loaded major histocompatibility complex (pMHC). We then emphasize the role of mechanical forces in (i) allosteric strengthening of the TCR–pMHC interaction in amplifying ligand discrimination during T cell antigen recognition prior to activation and (ii) T cell interactions with the extracellular matrix. We then describe approaches to design eTCRs, CARs, and biomaterials to exploit TCR mechanosensitivity in order to potentiate T cell manufacturing and function in adoptive T cell immunotherapy.

中文翻译：

---

机械力放大 T 细胞激活和功能中的 TCR 机械转导

过继性 T 细胞免疫疗法，包括工程化 T 细胞受体 (eTCR) 和嵌合抗原受体 (CAR) T 细胞免疫疗法，已显示出治疗部分血液恶性肿瘤的功效，在实体瘤中表现出希望，并具有许多其他潜在应用，例如纤维化、自身免疫和再生医学。虽然免疫工程的重点是设计生物材料来提供生化线索来操纵 T 细胞离体和体内，但调节其生物学的机械线索在很大程度上被低估了。这篇综述强调了机械力对几种对 T 细胞功能至关重要的受体-配体相互作用的贡献，重点关注 TCR 肽负载的主要组织相容性复合体 (pMHC)。然后，我们强调了机械力在以下方面的作用：(i) TCR-pMHC 相互作用的变构强化，在激活前 T 细胞抗原识别期间放大配体辨别；(ii) T 细胞与细胞外基质的相互作用。然后，我们描述了设计 eTCR、CAR 和生物材料的方法，以利用 TCR 机械敏感性来增强 T 细胞的制造和过继性 T 细胞免疫治疗中的功能。