The dynamic interplay between tumor cells and γδT cells within the tumor microenvironment (TME) significantly influences disease progression and immunotherapy outcome. Here, we delved into the modulation of γδT-cell activation by tumor cell ligands CD112 and CD155, which interact with the activating receptor DNAM-1 on γδT cells. Spatial and single cell RNA sequencing (scRNA-seq), as well as spatial metabolome analysis, from neuroblastoma (NB) revealed that the expression levels and localization of CD112 and CD155 varied across and within tumors, correlating with differentiation status, metabolic pathways, and ultimately disease prognosis and patient survival. Both in vivo tumor xenograft experiments and in vitro co-culture experiments demonstrated that a high CD112/CD155 expression ratio in tumors enhanced γδT-cell-mediated cytotoxicity, while a low-ratio fostered tumor resistance. Mechanistically, CD112 sustained DNAM-1-mediated γδT-cell activation, whereas CD155 downregulated DNAM-1 expression via TRIM21-mediated ubiquitin proteasomal degradation. By interacting with tumor cells differentially expressing CD112 and CD155, intratumoral γδT cells exhibited varying degrees of activation and DNAM-1 expression, representing three major functional subsets. This study underscores the complexity of tumor-immune crosstalk, offering insights into how tumor heterogeneity shapes the immune landscape.

中文翻译：

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空间和单细胞分析揭示了指导瘤内 γδT 细胞活性的 DNAM-1 受体-配体相互作用的异质性


肿瘤微环境 （TME） 中肿瘤细胞和 γδT 细胞之间的动态相互作用显着影响疾病进展和免疫治疗结果。在这里，我们深入研究了肿瘤细胞配体 CD112 和 CD155 对 γδT 细胞活化的调节，它们与 γδT 细胞上的激活受体 DNAM-1 相互作用。来自神经母细胞瘤 （NB） 的空间和单细胞 RNA 测序 （scRNA-seq） 以及空间代谢组分析显示，CD112 和 CD155 的表达水平和定位在肿瘤之间和肿瘤内不同，与分化状态、代谢途径相关，并最终与疾病预后和患者生存相关。体内肿瘤异种移植实验和体外共培养实验均表明，肿瘤中高 CD112/CD155 表达比值增强 γδT 细胞介导的细胞毒性，而低比值促进肿瘤耐药性。从机制上讲，CD112 维持 DNAM-1 介导的 γδT 细胞活化，而 CD155 通过 TRIM21 介导的泛素蛋白酶体降解下调 DNAM-1 表达。通过与差异表达 CD112 和 CD155 的肿瘤细胞相互作用，瘤内 γδT 细胞表现出不同程度的活化和 DNAM-1 表达，代表三个主要功能亚群。这项研究强调了肿瘤-免疫串扰的复杂性，为肿瘤异质性如何塑造免疫景观提供了见解。