Chimeric antigen receptor T-cell (CAR-T) therapies have shown potential in clinical trials for glioblastoma, yet treatment responses vary due to heterogeneous antigen expression and post-treatment immune escape. NKG2D−based CAR-T cells have exhibited a favorable safety profile in patients with hematologic malignancies and demonstrated potent antitumor activity in xenograft models, including those of glioblastoma. Nevertheless, glioma cells could evade immune recognition by downregulating or proteolytically shedding NKG2D ligands. To enhance the efficacy of NKG2D CAR-T therapy, we investigated its combination with preclinical agents capable of penetrating the blood-brain barrier that could upregulate NKG2D ligands on glioma cells. Our study revealed that resveratrol (RSV), a bioactive polyphenol, significantly increased the surface expression of NKG2D ligands on glioblastoma cells. RSV pretreatment sensitized these cells to NKG2D CAR-T-mediated killing in vitro. Additionally, the combination of RSV with NKG2D CAR-T cells demonstrated potent antitumor activity in vivo. Mechanistically, RSV potentially induced NKG2D ligand expression via activation of the p53 signaling pathway. These preclinical findings identify RSV as a promising pharmacological adjuvant that enhances NKG2D CAR-T efficacy in glioblastoma, supporting further translational and clinical evaluation of this combinatory approach.
Wei Liang, Yexiao Tang, M. A. Saliu et al.· Frontiers in Immunology· 0 citations
Papillary thyroid carcinoma (PTC) shows heterogeneous clinical behavior, and current clinicopathologic factors do not fully capture epithelial aggressiveness or tumor microenvironment (TME) remodeling. We integrated single-cell RNA-sequencing (scRNA-seq) datasets from normal thyroid tissue, primary PTC, and lymph-node metastases to construct a cross-stage cellular atlas and to characterize epithelial and T/NK-cell heterogeneity. Guided by the malignant epithelial program identified at single-cell resolution, we developed a four-gene risk signature in the TCGA-THCA cohort using Cox and LASSO regression. We further evaluated pathway activity, immune and stromal features, T-cell receptor (TCR) diversity, and exploratory in silico drug-response patterns, and we performed small interfering RNA (siRNA)-mediated knockdown of TMEM45A and STC1 in PTC cell lines. The integrated atlas revealed stage-related remodeling of epithelial, immune, and stromal compartments and identified a malignant epithelial state enriched for proliferation-, stress-, and migration-related programs. The four-gene signature was associated with overall survival stratification in TCGA-THCA after adjustment for age, sex, and stage. The high-risk group showed reduced immune infiltration, stronger stromal and epithelial-mesenchymal transition (EMT) signals, lower TCR diversity, and distinct predicted drug-response patterns. In vitro, TMEM45A or STC1 silencing suppressed proliferation and migration and altered EMT-related markers in PTC cells. These findings indicate that a malignant epithelial program defined by single-cell analysis can be translated into a four-gene signature associated with epithelial aggressiveness and TME remodeling in PTC, although its clinical utility requires validation in independent cohorts.
Ziyuan Wang, Shu Xu, Xuechen Chen et al.· Endocrine-Related Cancer· 0 citations