2025年11月19日，荷兰癌症研究所Daniel S. Peeper研究小组在《自然》杂志发表论文，宣布他们开发出来自临床样本的肿瘤反应性异型CD8 T细胞簇。

通过常规流式细胞术和成像流式细胞术，课题组发现从21例人类黑色素瘤转移中，课题组可以分离出异型细胞，包括CD8⁺ T细胞与一个或多个肿瘤细胞和/或抗原呈递细胞（APCs）相互作用。单细胞RNA测序分析显示，来自细胞的T细胞富含与肿瘤反应性和衰竭相关的基因特征。聚集的T细胞表现出增加的TCR克隆性，表明扩增，而TCR匹配的T细胞在与APCs结合时比与肿瘤细胞结合时表现出更多的衰竭和共调节。体外扩增的T细胞对自体黑色素瘤的杀伤活性平均增加了9倍，同时细胞因子的产生也增加了。在过继细胞转移到小鼠体内后，来自簇的T细胞显示出改善的患者源性黑色素瘤控制，这与T细胞浸润和激活增加有关。

总之，这些结果表明，肿瘤反应性CD8⁺ T细胞在具有肿瘤细胞和/或APCs的功能细胞中富集，并且可以从临床样品中分离和扩增。通常在流式细胞术中被单细胞门控排除在外，这些不同的异型T细胞细胞仪是破译功能性肿瘤-免疫细胞相互作用的有价值的证据，也可能在治疗上进行探索。

据悉，新出现的证据表明CD8⁺ T细胞与肿瘤细胞接近度和抗肿瘤免疫反应之间存在相关性。然而，目前尚不清楚这些细胞是否作为功能性细胞存在，可以从临床样本中分离出来。

附：英文原文

Title: Tumour-reactive heterotypic CD8 T cell clusters from clinical samples

Author: Ibez-Molero, Sofa, Veldman, Johanna, Simon Nieto, Juan, Traets, Joleen J. H., George, Austin, Hoefakker, Kelly, Karomi, Anita, Harkes, Rolf, van den Broek, Bram, Pack, Su Min, Tas, Liselotte, Visser, Nils L., van Hal-van Veen, Susan E., Alndiga-Mrida, Paula, Alkemade, Maartje, Seignette, Iris M., Tissier, Renaud, Nieuwland, Marja, van Baalen, Martijn, Poniak, Joanna, Mul, Erik, Tol, Simon, Stenqvist, Sofia, Nilsson, Lisa M., Nilsson, Jonas A., Haanen, John B. A. G., van Houdt, Winan J., Peeper, Daniel S.

Issue&Volume: 2025-11-19

Abstract: Emerging evidence suggests a correlation between CD8+ T cell–tumour cell proximity and anti-tumour immune response1,2. However, it remains unclear whether these cells exist as functional clusters that can be isolated from clinical samples. Here, using conventional and imaging flow cytometry, we show that from 21 out of 21 human melanoma metastases, we could isolate heterotypic clusters, comprising CD8+ T cells interacting with one or more tumour cells and/or antigen-presenting cells (APCs). Single-cell RNA-sequencing analysis revealed that T cells from clusters were enriched for gene signatures associated with tumour reactivity and exhaustion. Clustered T cells exhibited increased TCR clonality indicative of expansion, whereas TCR-matched T cells showed more exhaustion and co-modulation when conjugated to APCs than when conjugated to tumour cells. T cells that were expanded from clusters ex vivo exerted on average ninefold increased killing activity towards autologous melanomas, which was accompanied by enhanced cytokine production. After adoptive cell transfer into mice, T cells from clusters showed improved patient-derived melanoma control, which was associated with increased T cell infiltration and activation. Together, these results demonstrate that tumour-reactive CD8+ T cells are enriched in functional clusters with tumour cells and/or APCs and that they can be isolated and expanded from clinical samples. Typically excluded by single-cell gating in flow cytometry, these distinct heterotypic T cell clusters are a valuable source to decipher functional tumour–immune cell interactions and may also be therapeutically explored.

DOI: 10.1038/s41586-025-09754-w

Source: https://www.nature.com/articles/s41586-025-09754-w