肿瘤细胞治疗研究
英文原题：IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation.
IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation.
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这些结果表明，IL-15 可能促进 Tpex 细胞的自我更新，这具有重要的治疗意义。
在慢性感染和癌症中，耗竭的CD8 T细胞表现出异质性亚群。TCF1+PD-1+祖细胞样耗竭CD8 T细胞（Tpex）能够自我更新，并产生保留效应功能的Tim-3+PD-1+终末分化CD8 T细胞。因此，Tpex细胞对于在持续抗原刺激期间维持抗原特异性CD8 T细胞池至关重要，并且只有它们对PD-1靶向治疗有反应。尽管它们有潜力成为免疫干预的关键治疗靶点，但控制病毒特异性Tpex细胞维持的机制仍有待确定。我们观察到，在感染淋巴细胞性脉络丛脑膜炎病毒（LCMV）的慢性感染小鼠中，感染后一年（p.i.）脾脏中的Tpex细胞数量比感染后三个月时约少10倍。与记忆CD8 T细胞类似，在慢性LCMV感染期间，已发现Tpex细胞在淋巴器官，尤其是骨髓中进行自我更新。此外，离体IL-15处理优先诱导Tpex细胞而非终末分化亚群的增殖。有趣的是，对离体IL-15处理后与处理前的LCMV特异性耗竭CD8 T细胞进行单细胞RNA测序分析显示，在Tpex和Ttex亚群中，核糖体相关基因表达增加，而与TCR信号通路和凋亡相关的基因表达减少。对慢性LCMV感染小鼠外源性给予IL-15也显著增加了脾脏和骨髓中Tpex细胞的自我更新。此外，我们评估了肾细胞癌患者CD8TIL（肿瘤浸润淋巴细胞）对IL-15的反应性。与我们从小鼠慢性病毒感染中获得的数据相似，PD-1+ CD8 TIL中Tpex亚群在离体IL-15处理后的扩增显著高于终末分化亚群。这些结果表明，IL-15可以促进Tpex细胞的自我更新，这具有重要的治疗意义。
In chronic infections and cancer, exhausted CD8 T cells exhibit heterogeneous subpopulations. TCF1+PD-1+ progenitor exhausted CD8 T cells (Tpex) can self-renew and give rise to Tim-3+PD-1+ terminally differentiated CD8 T cells that retain their effector functions. Tpex cells are thus essential to maintaining a pool of antigen-specific CD8 T cells during persistent antigenic stimulation, and only they respond to PD-1-targeted therapy. Despite their potential as a crucial therapeutic target for immune interventions, the mechanisms controlling the maintenance of virus-specific Tpex cells remain to be determined. We observed approximately 10-fold fewer Tpex cells in the spleens of mice chronically infected with lymphocytic choriomeningitis virus (LCMV) one-year post-infection (p.i.) than at three months p.i. Similar to memory CD8 T cells, Tpex cells have been found to undergo self-renewal in the lymphoid organs, prominently the bone marrow, during chronic LCMV infection. Furthermore, ex vivo treatment with IL-15 preferentially induced the proliferation of Tpex cells rather than the terminally differentiated subsets. Interestingly, single-cell RNA sequencing analysis of LCMV-specific exhausted CD8 T cells after ex vivo IL-15 treatment compared with those before treatment revealed increased expression of ribosome-related genes and decreased expression of genes associated with the TCR signaling pathway and apoptosis in both Tpex and Ttex subsets. The exogenous administration of IL-15 to chronically LCMV-infected mice also significantly increased self-renewal of Tpex cells in the spleen and bone marrow. In addition, we assessed the responsiveness of CD8 tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma patients to IL-15. Similar to the data we obtained from chronic viral infection in mice, the expansion of the Tpex subset of PD-1+ CD8 TILs upon ex vivo IL-15 treatment was significantly higher than that of the terminally differentiated subset. These results show that IL-15 could promote self-renewal of Tpex cells, which has important therapeutic implications.
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