CD8(+) T cells maintain killing of MHC-I-negative tumor cells through the NKG2D-NKG2DL axis.
CD8(+) T cells maintain killing of MHC-I-negative tumor cells through the NKG2D-NKG2DL axis.
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DOI：
10.1038/s43018-023-00600-4
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发表时间：
2023-09
期刊：
影响因子：
22.7
通讯作者：
Fecci, Peter E. E.
中科院分区：
文献类型：
--
作者：
Lerner, Emily C. C.;Woroniecka, Karolina I. I.;D'Anniballe, Vincent M. M.;Wilkinson, Daniel S. S.;Mohan, Aditya A. A.;Lorrey, Selena J. J.;Waibl-Polania, Jessica;Wachsmuth, Lucas P. P.;Miggelbrink, Alexandra M. M.;Jackson, Joshua D. D.;Cui, Xiuyu;Raj, Jude A. A.;Tomaszewski, William H. H.;Cook, Sarah L. L.;Sampson, John H. H.;Patel, Anoop P. P.;Khasraw, Mustafa;Gunn, Michael D. D.;Fecci, Peter E. E.
细胞免疫和抗肿瘤免疫的公认范例依赖于 CD8+ T 细胞识别靶细胞主要组织相容性复合物 (MHC) I 类 (MHC-I) 分子中存在的同源抗原来杀死肿瘤细胞。同样，肿瘤免疫逃逸的经典描述机制是肿瘤 MHC-I 下调。在这里，我们报告 CD8+ T 细胞保持杀死完全缺乏 MHC-I 表达的肿瘤细胞的能力。事实证明，这种能力取决于 T 细胞自然杀伤组 2D (NKG2D) 和肿瘤 NKG2D 配体 (NKG2DL) 之间的相互作用，后者在 MHC 缺失变体上高度表达。在这些情况下，肿瘤细胞的杀伤作用必然是与抗原无关的，尽管需要事先进行 T 细胞抗原特异性激活，并且可以由骨髓细胞甚至邻近的 MHC 充足的肿瘤细胞提供。通过这种方式，适应性启动可以引发先天杀伤。这些机制在小鼠体内以及体外人类肿瘤系统中都很活跃，并且可以通过 NKG2D 敲除或阻断来消除。这些研究挑战了长期存在的观念，即MHC-I的下调是肿瘤免疫逃逸的可行手段，而是将NKG2D-NKG2DL轴确定为增强T细胞依赖性抗肿瘤免疫的治疗靶点，以对抗MHC缺失变异。 Fecci 及其同事表明，失去 MHC-I（免疫逃逸的主要机制）的肿瘤细胞易于被 CD8+ T 细胞通过不依赖 MHC-I 的替代途径（通过 NKG2D 和 NKG2DL 相互作用以及颗粒酶）杀死。
The accepted paradigm for both cellular and anti-tumor immunity relies upon tumor cell killing by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex (MHC) class I (MHC-I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, we report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell natural killer group 2D (NKG2D) and tumor NKG2D ligands (NKG2DLs), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell killing in these instances is antigen independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice as well as in vitro in human tumor systems and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape and instead identify the NKG2D–NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC-loss variants. Fecci and colleagues show that tumor cells having lost MHC-I, a major mechanism of immune escape, are amenable to killing by CD8+ T cells through an MHC-I-independent, alternative pathway via NKG2D and NKG2DL interaction and granzyme.
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