Hor Jyh Liang, Schrom Edward C, Wong-Rolle Abigail, Vistain Luke, Shang Wanjing, Dong Qiang, Zhao Chen, Jin Chengcheng, Germain Ronald N
Lymphocyte Biology Section, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA.
Thoracic and GI Malignancies Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
Nature. 2026 Jan;649(8095):194-204. doi: 10.1038/s41586-025-09440-x. Epub 2025 Nov 26.
Stem-like progenitors are self-renewing cytotoxic T cells that expand as effector cells during successful checkpoint immunotherapy. Emerging evidence suggests that tumour-draining lymph nodes support the continuous generation of these stem-like cells that replenish tumour sites and are a key source of expanded effector populations, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Here, using advanced three-dimensional multiplex immunofluorescence imaging, we identify antigen-presentation niches in tumour-draining lymph nodes that support the expansion, maintenance and affinity evolution of TCF-1PD-1SLAMF6 stem-like CD8 T cells. Contrary to the prevailing view that persistent T cell receptor (TCR) signalling drives terminal effector differentiation, prolonged antigen engagement days beyond initial priming sustains the proliferation and self-renewal of these stem-like T cells in vivo. The inhibitory PD-1 pathway has a central role in this process through fine-tuning the TCR signal input that enables the selective expansion of high-affinity TCR stem-like clones as a renewable source of effector cells. PD-1 blockade disrupts this tuning, leading to terminal differentiation or death of the most avid anti-tumour stem-like cells. Our results therefore reveal a relationship between TCR ligand affinity recognition, a key negative-feedback regulatory loop and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 blockade during cancer immunotherapy provides a short-term anti-tumour effect at the cost of diminishing efficacy due to progressive loss of these critical high-affinity precursors.
干细胞样前体细胞是自我更新的细胞毒性T细胞，在成功的检查点免疫治疗期间会作为效应细胞扩增。新出现的证据表明，肿瘤引流淋巴结支持这些干细胞样细胞的持续生成，这些细胞会补充肿瘤部位，并且是扩增的效应细胞群体的关键来源，这凸显了了解哪些因素促进和维持T细胞处于干细胞样状态的重要性。在这里，我们使用先进的三维多重免疫荧光成像技术，在肿瘤引流淋巴结中识别出支持TCF-1⁺PD-1⁻SLAMF6⁺干细胞样CD8 T细胞扩增、维持和亲和力进化的抗原呈递微环境。与普遍认为的持续性T细胞受体（TCR）信号驱动终末效应细胞分化的观点相反，在初次致敏后的数天内延长抗原接触时间可在体内维持这些干细胞样T细胞的增殖和自我更新。抑制性PD-1通路在这一过程中起核心作用，它通过微调TCR信号输入，使高亲和力TCR干细胞样克隆选择性扩增，成为效应细胞的可再生来源。PD-1阻断会破坏这种调节，导致最活跃的抗肿瘤干细胞样细胞终末分化或死亡。因此，我们的结果揭示了TCR配体亲和力识别、一个关键的负反馈调节环与T细胞干性编程之间的关系。此外，这些发现还引发了关于癌症免疫治疗期间抗PD-1阻断是否以这些关键的高亲和力前体逐渐丧失为代价，以短期抗肿瘤效果换取疗效降低的问题。
