Dynamics of Immune Responses Unit, Equipe Labéllisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM U668, rue du Dr Roux, 75015 Paris, France; Cellule Pasteur, University Paris Diderot, Sorbonne Paris Cité, 75015 Paris, France.
Dynamics of Immune Responses Unit, Equipe Labéllisée Ligue Contre le Cancer, Institut Pasteur, 75015 Paris, France; INSERM U668, rue du Dr Roux, 75015 Paris, France.
Immunity. 2016 Jan 19;44(1):143-154. doi: 10.1016/j.immuni.2015.12.008. Epub 2016 Jan 12.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a curative treatment for hematologic malignancies, relies on donor cytotoxic T lymphocyte (CTL)-mediated graft-versus-leukemia (GVL) effect. Major complications of HSCT are graft-versus-host disease (GVHD) that targets specific tissues and tumor relapses. However, the mechanisms dictating the anatomical features of GVHD and GVL remain unclear. Here, we show that after HSCT, CTLs exhibited different killing activity in distinct tissues, being highest in the liver and lowest in lymph nodes. Differences were imposed by the microenvironment, partly through differential PD-1 ligand expression, which was strongly elevated in lymph nodes. Two-photon imaging revealed that PD-1 blockade restored CTL sensitivity to antigen and killing in lymph nodes. Weak CTL activity in lymph nodes promoted local tumor escape but could be reversed by anti-PD-1 treatment. Our results uncover a mechanism generating an anatomical segregation of CTL activity that might dictate sites of GVHD and create niches for tumor escape.
异基因造血干细胞移植（allo-HSCT）是治疗血液系统恶性肿瘤的一种有治愈可能的方法，它依赖于供体细胞毒性 T 淋巴细胞（CTL）介导的移植物抗白血病（GVL）效应。HSCT 的主要并发症是移植物抗宿主病（GVHD），它针对特定的组织，还有肿瘤复发。然而，决定 GVHD 和 GVL 解剖特征的机制尚不清楚。在这里，我们发现 HSCT 后，CTL 在不同组织中的杀伤活性不同，在肝脏中最高，在淋巴结中最低。这种差异是由微环境造成的，部分原因是 PD-1 配体表达的差异，在淋巴结中强烈升高。双光子成像显示，PD-1 阻断恢复了 CTL 对淋巴结中抗原的敏感性和杀伤能力。淋巴结中 CTL 活性较弱会促进局部肿瘤逃逸，但通过抗 PD-1 治疗可以逆转。我们的研究结果揭示了一种产生 CTL 活性的解剖分离的机制，这种机制可能决定 GVHD 的部位，并为肿瘤逃逸创造生态位。
