Ion channels of T cells (Kv1.3, KCa3.1, and CRAC) participate in the regulation of activation and effector functions via modulation of the Ca2+-dependent pathway. T cells expressing chimeric antigen receptors (CAR T cells) showed a remarkable role in anti-tumor therapy, especially in the treatment of chemotherapy-resistant liquid cancers. Nevertheless, many challenges remain to be overcome to improve the treatment for solid tumors. In this study, we assessed the expression and role of ion channels in CAR T cells. We found that HER2-specific CAR T cells had higher KCa3.1 conductance compared to the non-transduced (NT, control) cells, which was more prominent in the CD8+population (CD4+cell also showed elevation). Conversely, the Kv1.3 expression level was the same for all cell types (CD4+, CD8+, CAR, and NT). Single-cell Ca2+imaging revealed that thapsigargin-induced SOCE via CRAC is suppressed in CD8+CAR T cells, unlike for CD4+and CD8+NT cells. To dissect the functional role of Kv1.3 and KCa3.1, we used specific antagonists (Kv1.3: Vm24; KCa3.1: TRAM-34): the target cell elimination capacity of the CD8+CAR T cells was improved either by blocking KCa3.1 or Kv1.3. These results imply that ion channels could be a target in CAR T cell immunotherapy elaboration.
T细胞离子通道（Kv1.3、KCa3.1和CRAC）通过调控钙离子依赖通路参与T细胞活化及效应功能的调节。表达嵌合抗原受体的T细胞（CAR T细胞）在抗肿瘤治疗中展现出显著作用，尤其在化疗耐药的血液肿瘤治疗中表现突出。然而，在实体瘤治疗领域仍存在诸多挑战亟待突破。本研究评估了离子通道在CAR T细胞中的表达及功能。研究发现，与未转导的对照组细胞相比，HER2特异性CAR T细胞具有更高的KCa3.1电导，这种现象在CD8+亚群中尤为显著（CD4+细胞也呈现升高趋势）。相反，所有细胞类型（CD4+、CD8+、CAR及对照组）的Kv1.3表达水平基本一致。单细胞钙成像显示，在CD8+CAR T细胞中，毒胡萝卜素通过CRAC通道诱导的钙库操纵性钙内流受到抑制，而CD4+及CD8+对照组细胞则无此现象。为解析Kv1.3与KCa3.1的功能作用，我们采用特异性拮抗剂（Kv1.3：Vm24；KCa3.1：TRAM-34）进行研究，发现阻断KCa3.1或Kv1.3均能增强CD8+CAR T细胞的靶细胞清除能力。这些结果表明，离子通道可作为CAR T细胞免疫疗法优化的重要靶点。
Inhibition of K+Channels Affects the Target Cell Killing Potential of CAR T Cells
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