journal contribution
posted on 2025-01-15, 08:21 authored by Xiaolin Wang, Hui Wang, Zhengjing Lu, Xiangjun Liu, Wenjia Chai, Wei Wang, Jun Feng, Shen Yang, Wei Yang, Haiyan Cheng, Chenghao Chen, Shihan Zhang, Nian Sun, Qiaoyin Liu, Qiliang Li, Wenqi Song, Fang Jin, Qi Zeng, Shengcai Wang, Yan Su, Huanmin Wang, Xin Ni, Jingang Gui <p>Supplementary Figure 10 Identification of Tet-on system, ROC curves and survival curves of different groups for NB tumor. (A) and (B) The variation of CD112 and CD155 expression in SK-N-BE2 cells treated with different concentration of doxycycline (0, 2 nM, 20 nM, 200 nM, 2 μM, 20 μM) is detected by qPCR and Western blot. (C) ROC curves are generated for CD112, CD155, and CD112/CD155 ratio to predict NB patient death, tumor risk or MYCN amplification. The results are expressed as the means ± SEMs from at least three independent experiments. Significant differences between groups are represented by ns no significance, * p < 0.05, ** p < 0.01 and *** p < 0.001.</p>
Funding
National Natural Science Foundation of China (NSFC)
History
ARTICLE ABSTRACT
The dynamic interplay between tumor cells and γδT cells within the tumor microenvironment significantly influences disease progression and immunotherapy outcome. In this study, 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, as well as spatial metabolomic analysis, from neuroblastoma 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 coculture experiments demonstrated that a high CD112/CD155 expression ratio in tumors enhanced γδT cell–mediated cytotoxicity, whereas a low ratio fostered tumor resistance. Mechanistically, CD112 sustained DNAM-1–mediated γδT-cell activation, whereas CD155 downregulated DNAM-1 expression via E3 ubiquitin ligase tripartite motif–containing 21–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 cross-talk, offering insights into how tumor heterogeneity shapes the immune landscape.Significance: Tumor cells in different intratumoral neighborhoods display divergent patterns of ligands that regulate γδT-cell activation, highlighting multilevel regulation of antitumor immunity resulting from the heterogeneity of intercellular interactions in the tumor microenvironment.
