Serniuck Nickolas J, Kapcan Eden, Moogk Duane, Moore Allyson E, Lake Benjamin P M, Denisova Galina, Hammill Joanne A, Bramson Jonathan L, Rullo Anthony F
Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON, Canada.
McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada.
Mol Ther Oncol. 2024 Jun 24;32(3):200842. doi: 10.1016/j.omton.2024.200842. eCollection 2024 Sep 19.
Proximity-induction of cell-cell interactions via small molecules represents an emerging field in basic and translational sciences. Covalent anchoring of these small molecules represents a useful chemical strategy to enforce proximity; however, it remains largely unexplored for driving cell-cell interactions. In immunotherapeutic applications, bifunctional small molecules are attractive tools for inducing proximity between immune effector cells like T cells and tumor cells to induce tumoricidal function. We describe a two-component system composed of electrophilic bifunctional small molecules and paired synthetic antigen receptors (SARs) that elicit T cell activation. The molecules, termed covalent immune recruiters (CIRs), were designed to affinity label and covalently engage SARs. We evaluated the utility of CIRs to direct anti-tumor function of human T cells engineered with three biologically distinct classes of SAR. Irrespective of the electrophilic chemistry, tumor-targeting moiety, or SAR design, CIRs outperformed equivalent non-covalent bifunctional adapters, establishing a key role for covalency in maximizing functionality. We determined that covalent linkage enforced early T cell activation events in a manner that was dependent upon each SARs biology and signaling threshold. These results provide a platform to optimize universal SAR-T cell functionality and more broadly reveal new insights into how covalent adapters modulate cell-cell proximity-induction.
通过小分子实现细胞间相互作用的邻近诱导是基础科学和转化科学中一个新兴的领域。这些小分子的共价锚定是一种用于增强邻近性的有用化学策略；然而，在驱动细胞间相互作用方面，这一策略在很大程度上仍未得到探索。在免疫治疗应用中，双功能小分子是诱导免疫效应细胞（如T细胞）与肿瘤细胞之间的邻近性以诱导杀肿瘤功能的有吸引力的工具。我们描述了一种由亲电双功能小分子和配对的合成抗原受体（SARs）组成的双组分系统，该系统可引发T细胞活化。这些分子被称为共价免疫招募剂（CIRs），旨在亲和标记并共价结合SARs。我们评估了CIRs指导用三种生物学上不同类别的SAR工程化改造的人T细胞的抗肿瘤功能的效用。无论亲电化学、肿瘤靶向部分或SAR设计如何，CIRs均优于等效的非共价双功能衔接子，确立了共价性在最大化功能方面的关键作用。我们确定共价连接以一种依赖于每个SARs生物学特性和信号阈值的方式强化了早期T细胞活化事件。这些结果提供了一个优化通用SAR-T细胞功能的平台，并更广泛地揭示了关于共价衔接子如何调节细胞间邻近诱导的新见解。
