在细胞和抗肿瘤免疫方面，公认的范式依赖于CD8+ T细胞通过识别在靶细胞主要组织相容性复合物（MHC-I）分子表达背景下的同源抗原来杀死肿瘤细胞。同样，肿瘤MHC-I下调是肿瘤免疫逃逸的经典机制之一。在这里，我们报告了CD8+ T细胞能够杀死完全缺乏MHC-I表达的肿瘤细胞的能力。这种能力实际上取决于T细胞自然杀伤群体2D（NKG2D）与肿瘤NKG2D配体（NKG2DLs）之间的相互作用，后者在MHC缺失变体上高度表达。必然地，这些情况下的肿瘤细胞杀伤是独立于抗原的，尽管之前需要T细胞抗原特异性激活，而这可以由髓细胞或甚至是旁边的MHC完整的肿瘤细胞提供。通过这种方式，适应性预激可以产生先天性杀伤。这些机制在小鼠体内以及人类肿瘤体外系统中都是活跃的，并且通过NKG2D基因敲除或阻断可被排除。这些研究挑战了长期以来认为MHC-I下调是肿瘤免疫逃逸的可行手段的观点，相反，确认了NKG2D-NKG2DL轴作为增强依赖MHC缺失变体的T细胞抗肿瘤免疫的治疗靶点。© 2023. 作者。

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.© 2023. The Author(s).