丹娜-法伯癌症研究所Catherine J. Wu.团队的一项最新研究认为三级淋巴结构含有干细胞样肿瘤特异性T细胞。该项研究成果发表在2026年7月22日出版的《自然》上。

在24例未经治疗的肾细胞癌（RCC）肿瘤中，研究团队发现，与TLS相比，含有TLS的肿瘤更严重地被衰竭的CD8⁺ T细胞浸润，并且具有减少的末端耗竭转录程序。在6例RCC肿瘤的微环境中扩增的554种T细胞克隆型的特异性筛选显示，82种TCRs对肿瘤细胞和/或RCC抗原具有反应性。肿瘤特异性T细胞克隆型的一个子集（12%）在TLSs中富集，这些克隆型表达了一个增加的干细胞样祖细胞衰竭程序，与有利的抗肿瘤免疫相关。

然而，在60例独立的RCC肿瘤中，含有TLS的肿瘤边缘的巨噬细胞具有推断的免疫抑制表型，并且在进一步分析的亚群中与假定的肿瘤反应性T细胞共定位，因此支持这种免疫逃避模式作为对T细胞免疫压力的平衡。他们的数据显示，TLSs是肿瘤特异性T细胞的储存库，具有干细胞样祖细胞特征，可以被T细胞免疫疗法利用。

据介绍，三级淋巴结构（TLSs）与实体肿瘤免疫检查点阻断反应的改善有关，但它们如何影响肿瘤特异性T细胞的表型特性尚不清楚。

附：英文原文

Title: Tertiary lymphoid structures harbour stem-like tumour-specific T cells

Author: Afeyan, Alexander B., Nagler, Adi, Tu, Chloe R., Roberti De Oliveira, Gabriel, Simsek, Berkay, Seager, Maxwell D., El Ahmar, Nourhan, Sax, Haley E., Lin, Emma, Sud, Amit, Borji, Mehdi, Forman, Cleo, Liu, Sophia, Ott, Patrick A., Choueiri, Toni K., Abelin, Jennifer G., Burack, Richard, Li, Shuqiang, Livak, Kenneth J., Tyekucheva, Svitlana, Keskin, Derin B., Chen, Fei, Atkins, Michael B., Simon, Jeremy M., Signoretti, Sabina, Oliveira, Giacomo, Braun, David A., Wu, Catherine J.

Issue&Volume: 2026-07-22

Abstract: Tertiary lymphoid structures (TLSs) are associated with improved responses to immune checkpoint blockade across solid tumours1,2, but how they impact the phenotypic properties of tumour-specific T cells remains unclear. Here we found, across 24 treatment-naive renal cell carcinoma (RCC) tumours, that TLS-containing tumours are more heavily infiltrated by exhausted CD8+ T cells and have a reduced terminal exhaustion transcriptional program compared with TLS tumours. Specificity screening of 554 T cell clonotypes expanded within the microenvironment of 6 RCC tumours revealed 82 TCRs that were reactive against tumour cells and/or RCC antigens. A subset of tumour-specific T cell clonotypes (12%) was enriched within TLSs, and these expressed an increased program of stem-like progenitor exhaustion, associated with favourable anti-tumour immunity. However, in 60 independent RCC tumours, macrophages within tumour margins of TLS-containing tumours had an inferred immunosuppressive phenotype and were colocalized with exhausted putative tumour-reactive T cells in a subgroup that was further analysed, therefore supporting this mode of immune evasion as a counterbalance to T cell immune pressure. Our data reveal that TLSs are reservoirs of tumour-specific T cells with stem-like progenitor features that could be leveraged by T cell immunotherapies.

DOI: 10.1038/s41586-026-10808-w

Source: https://www.nature.com/articles/s41586-026-10808-w