肿瘤诱导的自然杀伤细胞功能障碍是一个快速且可逆的过程，与免疫检查点的表达无关。
Tumor-induced natural killer cell dysfunction is a rapid and reversible process uncoupled from the expression of immune checkpoints.
发表日期：2024 Aug 30
作者：
Kévin Pouxvielh, Marie Marotel, Annabelle Drouillard, Marine Villard, Marion Moreews, Anna Bossan, Mathilde Poiget, Liliane Khoryati, Sarah Benezech, Lucie Fallone, Sarah Hamada, Noémi Rousseaux, Louis Picq, Yamila Rocca, Aurore Berton, Marine Teixeira, Anne-Laure Mathieu, Michelle Ainouze, Uzma Hasan, Alain Fournier, Olivier Thaunat, Antoine Marçais, Thierry Walzer
来源：
CYTOKINE & GROWTH FACTOR REVIEWS
摘要：
自然杀伤（NK）细胞在肿瘤进展过程中经常变得功能失调，但这种表型背后的分子机制仍不清楚。为了探索这一现象，我们建立了激活或不激活 NK 细胞的小鼠淋巴瘤模型。这两种肿瘤类型都会引发 I 型干扰素的产生，导致 NK 细胞中表达类似 T 细胞耗竭的特征，其中包括免疫检查点蛋白 (ICP)。然而，NK 细胞功能障碍仅发生在触发 NK 细胞激活的肿瘤模型中。此外，与阴性细胞相比，ICP 阳性 NK 细胞表现出更高的反应性。此外，NK 细胞功能障碍的发生迅速且暂时与 ICP 诱导无关，而 ICP 诱导是肿瘤生长过程中的后期事件。最后，当刺激停止时，NK 细胞反应性得以恢复，而白细胞介素 15 对这种恢复具有积极影响。因此，我们的数据表明 NK 细胞的反应性是动态控制的，并且 NK 细胞功能障碍是一个与 ICP 表达无关的可逆过程。
Natural killer (NK) cells often become dysfunctional during tumor progression, but the molecular mechanisms underlying this phenotype remain unclear. To explore this phenomenon, we set up mouse lymphoma models activating or not activating NK cells. Both tumor types elicited type I interferon production, leading to the expression of a T cell exhaustion-like signature in NK cells, which included immune checkpoint proteins (ICPs). However, NK cell dysfunction occurred exclusively in the tumor model that triggered NK cell activation. Moreover, ICP-positive NK cells demonstrated heightened reactivity compared to negative ones. Furthermore, the onset of NK cell dysfunction was swift and temporally dissociated from ICPs induction, which occurred as a later event during tumor growth. Last, NK cell responsiveness was restored when stimulation was discontinued, and interleukin-15 had a positive impact on this reversion. Therefore, our data demonstrate that the reactivity of NK cells is dynamically controlled and that NK cell dysfunction is a reversible process uncoupled from the expression of ICPs.