Department of Bioengineering, Imperial College London, London, SW7 2AZ, UK.
Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, 1066, Switzerland.
Adv Healthc Mater. 2022 Aug;11(16):e2200169. doi: 10.1002/adhm.202200169. Epub 2022 Jun 21.
No T cell receptor (TCR) T cell therapies have obtained clinical approval. The lack of strategies capable of selecting and recovering potent T cell candidates may be a contributor to this. Existing protocols for selecting TCR T cell clones for cell therapies such as peptide multimer methods have provided effective measurements on TCR affinities. However, these methods lack the ability to measure the collective strength of intercellular interactions (i.e., cellular avidity) and markers of T cell activation such as immunological synapse formation. This study describes a novel microfluidic fluid shear stress-based approach to identify and recover highly potent T cell clones based on the cellular avidity between living T cells and tumor cells. This approach is capable of probing approximately up to 10 000 T cell-tumor cell interactions per run and can recover potent T cells with up to 100% purity from mixed populations of T cells within 30 min. Markers of cytotoxicity, activation, and avidity persist when recovered high cellular avidity T cells are subsequently exposed to fresh tumor cells. These results demonstrate how microfluidic probing of cellular avidity may fast track the therapeutic T cell selection process and move the authors closer to precision cancer immunotherapy.
目前尚无获得临床批准的 T 细胞受体 (TCR) T 细胞疗法。缺乏能够选择和回收有效 T 细胞候选物的策略可能是造成这种情况的原因之一。用于选择 TCR T 细胞克隆进行细胞治疗的现有方案，如肽多聚体方法，已经提供了 TCR 亲和力的有效测量方法。然而，这些方法缺乏测量细胞间相互作用（即细胞亲合力）和 T 细胞活化标志物（如免疫突触形成）的集体强度的能力。本研究描述了一种基于微流控的新型流体切应力方法，用于根据活 T 细胞与肿瘤细胞之间的细胞亲合力来识别和回收高活性 T 细胞克隆。该方法每次运行可探测多达 10000 个 T 细胞-肿瘤细胞相互作用，并且能够在 30 分钟内从 T 细胞的混合群体中以高达 100%的纯度回收有效 T 细胞。当回收高细胞亲合力的 T 细胞随后暴露于新鲜肿瘤细胞时，细胞毒性、活化和亲合力标志物仍然存在。这些结果表明，细胞亲合力的微流控探测如何能够加速治疗性 T 细胞选择过程，并使作者更接近精准癌症免疫治疗。
