Adoptive T cell-transfer (ATC) therapy is a highly promising cancer-treatment approach. However, in vivo-administered T cells tend to disperse, with only a small proportion reaching the tumour. To remedy this, magnetic targeting of T cells has been recently explored. Magnetic nanoparticles (MNPs) functionalised with antibodies were attached to effector T cells and magnetically recruited to tumour sites under MRI guidance. In this study, we investigated whether 3-aminopropyl-triethoxysilane (APS)-coated MNPs directly attached to CD8+ T cell membranes could also magnetically target and accumulate tumour-specific CD8+ T cells in solid tumours using an external magnetic field (EMF). As it has been shown that T cells associated with APS-coated MNPs are retained in lymph nodes (LNs), and tumour-draining LNs are the most common sites of solid-tumour metastases, we further evaluated whether magnetic targeting of APS-MNP-loaded CD8+ T cells could cause them to accumulate in tumour-draining LNs. First, we show that antigen-specific CD8+ T cells preserve their antitumor activity in vitro when associated with APS-MNPs. Next, we demonstrate that the application of a magnetic field enhanced the retention of APS-MNP-loaded OT-I CD8+ T cells under flow conditions in vitro. Using a syngeneic mouse model, we found similar numbers of APS-MNP-loaded OT-I CD8+ T cells and OT-I CD8+ T cells infiltrating the tumour 14 days after cell transfer. However, when a magnet was placed near the tumour during the transfer of tumour-specific APS-MNP-loaded CD8+ T cells to improve tumour infiltration, a reduced percentage of tumour-specific T cells was found infiltrating the tumour 14 days after cell transfer, which was reflected in a smaller reduction in tumour size compared to tumour-specific CD8+ T cells transferred with or without MNPs in the absence of a magnetic field. Nonetheless, magnet placement near the tumour site during cell transfer induced infiltration of activated tumour-specific CD8+ T cells in tumour-draining LNs, which remained 14 days after cell transfer. The use of an EMF to improve targeting of tumour-specific T cells modified with APS-MNPs reduced the percentage of these cells infiltrating the tumour, but promoted the retention and the persistence of these cells in the tumour-draining LNs.

中文翻译：

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磁性靶向靶向过继转移的装载有肿瘤特异性纳米颗粒的CD8 ⁺ T细胞在癌症小鼠模型中不会改善其肿瘤浸润，但会促进这些细胞在引流肿瘤的淋巴结中保留

过继性T细胞转移（ATC）治疗是一种很有前途的癌症治疗方法。然而，体内施用的T细胞趋于分散，只有一小部分到达肿瘤。为了解决这个问题，最近已经探索了对T细胞的磁性靶向。用抗体功能化的磁性纳米颗粒（MNP）附着在效应T细胞上，并在MRI指导下磁性募集到肿瘤部位。在这项研究中，我们调查了是否直接附着于CD8 + T细胞膜的3-氨丙基-三乙氧基硅烷（APS）涂层的MNPs还能利用外部磁场（EMF）磁性靶向并积聚在实体瘤中的肿瘤特异性CD8 + T细胞。如已证明，与APS包覆的MNP相关的T细胞保留在淋巴结（LN）中，肿瘤引流的LNs是实体瘤转移的最常见部位，我们进一步评估了APS-MNP加载的CD8 + T细胞的磁靶向作用是否会导致它们在肿瘤引流的LNs中积聚。首先，我们显示抗原特异性CD8 + T细胞在与APS-MNP结合时在体外保留了其抗肿瘤活性。接下来，我们证明了磁场的应用增强了体外流动条件下载有APS-MNP的OT-1 CD8 + T细胞的保留。使用同系小鼠模型，我们发现细胞转移后14天，APS-MNP加载的OT-1 CD8 + T细胞和OT-1 CD8 + T细胞的浸润数量相似。但是，如果在转移肿瘤特异性APS-MNP的CD8 + T细胞转移过程中将磁体放置在肿瘤附近，以改善肿瘤浸润，在转移细胞后14天，发现浸润肿瘤的肿瘤特异性T细胞百分比降低，这反映出与没有磁场或没有MNPs的肿瘤特异性CD8 + T细胞相比，在没有磁场的情况下，肿瘤大小的减小较小。但是，在细胞转移过程中，磁铁在肿瘤部位附近的放置会导致肿瘤转移引流的LNs中活化的肿瘤特异性CD8 + T细胞浸润，这在细胞转移后仍保持14天。使用EMF来改善用APS-MNPs修饰的肿瘤特异性T细胞的靶向作用，减少了这些细胞浸润肿瘤的百分比，但促进了这些细胞在引流肿瘤的LN中的保留和持久性。与在没有磁场的情况下转移或不转移MNPs的肿瘤特异性CD8 + T细胞相比，肿瘤缩小的幅度较小。但是，在细胞转移过程中，磁铁在肿瘤部位附近的放置会导致肿瘤转移引流的LNs中活化的肿瘤特异性CD8 + T细胞浸润，这在细胞转移后仍保持14天。使用EMF来改善用APS-MNPs修饰的肿瘤特异性T细胞的靶向作用，减少了这些细胞浸润肿瘤的百分比，但促进了这些细胞在引流肿瘤的LN中的保留和持久性。与在没有磁场的情况下转移或不转移MNPs的肿瘤特异性CD8 + T细胞相比，肿瘤缩小的幅度较小。但是，在细胞转移过程中，磁体在肿瘤部位附近的放置会导致肿瘤转移引流的LNs中活化的肿瘤特异性CD8 + T细胞浸润，这在细胞转移后仍保持了14天。使用EMF来改善用APS-MNPs修饰的肿瘤特异性T细胞的靶向作用，减少了这些细胞浸润肿瘤的百分比，但促进了这些细胞在引流肿瘤的LN中的保留和持久性。但是，在细胞转移过程中，磁铁在肿瘤部位附近的放置会导致肿瘤转移引流的LNs中活化的肿瘤特异性CD8 + T细胞浸润，这在细胞转移后仍保持14天。使用EMF来改善用APS-MNPs修饰的肿瘤特异性T细胞的靶向作用，减少了这些细胞浸润肿瘤的百分比，但促进了这些细胞在引流肿瘤的LN中的保留和持久性。但是，在细胞转移过程中，磁铁在肿瘤部位附近的放置会导致肿瘤转移引流的LNs中活化的肿瘤特异性CD8 + T细胞浸润，这在细胞转移后仍保持14天。使用EMF来改善用APS-MNPs修饰的肿瘤特异性T细胞的靶向作用，减少了这些细胞浸润肿瘤的百分比，但促进了这些细胞在引流肿瘤的LN中的保留和持久性。