Exhaustion and mitochondrial dysfunction can limit the effector function of T cells and their ability to kill solid tumors, an effect that tumor cells are thought to capitalize on by sucking mitochondria out of immune cells via tunneling nanotube connections (membrane protrusions that can connect cells over long distances). Data now published in Cell show how these nanotubes can be utilized in an immunotherapeutic context to reverse the flow of mitochondria to support T cell effector functions against tumors. Using highly detailed field-emission scanning electron microscopy, the researchers observed these nanotube structures linking co-cultured CD8⁺ T cells to bone marrow stromal cells (BMSC). In addition, they could see mitochondria inside the nanotubes using confocal microscopy and identified BMSC donor mitochondria in the T cells. The result of this mitochondrial transfer from BMSCs to CD8⁺ T cells was increased mitochondrial content and general metabolic fitness. Recipient T cells infiltrated tumors more efficiently, had improved effector functions and increased tumor-killing capacity when injected into mice, and were less susceptible to exhaustion in the tumor microenvironment. The researchers translated these findings further by showing how this BMSC mitochondrial transfer method can also enhance a CD19 chimeric antigen receptor (CAR) T cell.

Original reference: Cell https://doi.org/10.1016/j.cell.2024.08.029 (2024)

耗竭和线粒体功能障碍会限制 T 细胞的效应功能及其杀死实体瘤的能力，肿瘤细胞被认为可以通过隧道纳米管连接（可以长距离连接细胞的膜突起）从免疫细胞中吸出线粒体来利用这种效应。现在发表在 Cell 上的数据显示了如何在免疫治疗环境中利用这些纳米管来逆转线粒体的流动，以支持针对肿瘤的 T 细胞效应器功能。研究人员使用高度详细的场发射扫描电子显微镜观察了这些将共培养的 CD8⁺ T 细胞与骨髓基质细胞 （BMSC） 相连的纳米管结构。此外，他们可以使用共聚焦显微镜看到纳米管内的线粒体，并在 T 细胞中鉴定出 BMSC 供体线粒体。这种线粒体从 BMSCs 转移到 CD8⁺ T 细胞的结果是线粒体含量和一般代谢适应性增加。受体 T 细胞更有效地浸润肿瘤，注射到小鼠体内时具有更好的效应功能并增加肿瘤杀伤能力，并且在肿瘤微环境中不易耗竭。研究人员通过展示这种 BMSC 线粒体转移方法如何也可以增强 CD19 嵌合抗原受体 （CAR） T 细胞，进一步诠释了这些发现。

原始参考：细胞 https://doi.org/10.1016/j.cell.2024.08.029 （2024）