Hor Jyh Liang, Schrom Edward C, Wong-Rolle Abigail, Vistain Luke, Shang Wanjing, Dong Qiang, Zhao Chen, Jin Chengcheng, Germain Ronald N
bioRxiv. 2024 Aug 6:2024.08.02.606241. doi: 10.1101/2024.08.02.606241.
Stem-like progenitors are a critical subset of cytotoxic T cells that self-renew and give rise to expanded populations of effector cells critical for successful checkpoint blockade immunotherapy. Emerging evidence suggests that the tumor-draining lymph nodes can support the continuous generation of these stem-like cells that replenish the tumor sites and act as a critical source of expanded effector populations, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Using advanced 3D multiplex immunofluorescence imaging, here we identified antigen-presentation niches in tumor-draining lymph nodes that support the expansion, maintenance, and affinity evolution of a unique population of TCF-1+PD-1+SLAMF6 stem-like CD8+ T cells. Our results show that contrary to the prevailing view that persistent TCR signaling drives terminal effector differentiation, prolonged antigen engagement well beyond the initial priming phase sustained the proliferation and self-renewal of these stem-like T cells . The inhibitory PD-1 pathway plays a central role in this process by mediating the fine-tuning of TCR and co-stimulatory signal input that enables selective expansion of high affinity TCR stem-like clones, enabling them to act as a renewable source of high affinity effector cells. PD-1 checkpoint blockade disrupts this fine tuning of input signaling, leading to terminal differentiation to the effector state or death of the most avid anti-tumor stem-like cells. Our results thus reveal an unexpected 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 checkpoint blockade during cancer immunotherapy provides a short-term anti-tumor effect that comes at the cost of diminishing efficacy due to progressive loss of these critical high affinity stem-like precursors.
干细胞样祖细胞是细胞毒性T细胞的一个关键亚群，它们能够自我更新，并产生大量效应细胞，这些效应细胞对于成功的检查点阻断免疫疗法至关重要。新出现的证据表明，肿瘤引流淋巴结可以支持这些干细胞样细胞的持续生成，这些细胞补充肿瘤部位，并作为扩增效应细胞群体的关键来源，这突出了了解哪些因素促进和维持T细胞处于干细胞样激活状态的重要性。利用先进的3D多重免疫荧光成像技术，我们在此确定了肿瘤引流淋巴结中的抗原呈递微环境，该微环境支持独特的TCF-1+PD-1+SLAMF6干细胞样CD8+T细胞群体的扩增、维持和亲和力进化。我们的结果表明，与普遍认为持续的TCR信号驱动终末效应细胞分化的观点相反，在初始致敏阶段之后很长时间的持续抗原接触维持了这些干细胞样T细胞的增殖和自我更新。抑制性PD-1通路在这一过程中发挥核心作用，它通过介导TCR和共刺激信号输入的微调，使高亲和力TCR干细胞样克隆能够选择性扩增，使其能够作为高亲和力效应细胞的可再生来源。PD-1检查点阻断破坏了输入信号的这种微调，导致终末分化为效应细胞状态或最活跃的抗肿瘤干细胞样细胞死亡。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细胞干性编程之间意想不到的关系。此外，这些发现引发了关于癌症免疫治疗期间抗PD-1检查点阻断是否提供短期抗肿瘤效果的问题，而这种短期效果是以这些关键的高亲和力干细胞样前体的逐渐丧失导致疗效降低为代价的。
