DSG2 Expression Marks a Stromal-Immune Organizational State in Head and Neck Squamous Cell Carcinoma
CANCERS, cilt.18, sa.16, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 18 Sayı: 16
- Basım Tarihi: 2026
- Doi Numarası: 10.3390/cancers18162611
- Dergi Adı: CANCERS
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, CINAHL, EMBASE, Academic Search Ultimate (EBSCO), Natural Science Collection (ProQuest), Biological Science Database (ProQuest), Biomedical Reference Collection: Corporate Edition (EBSCO)
- Recep Tayyip Erdoğan Üniversitesi Adresli: Hayır
Özet
Background/Objectives: Immune exclusion in head and neck squamous cell carcinoma (HNSCC) limits immunotherapy efficacy, yet the molecular determinants of stromal-immune organization remain incompletely characterized. The desmosomal cadherin DSG2 is highly expressed in squamous epithelium; its role in shaping the tumor microenvironment (TME) is unknown. Methods: We integrated bulk RNA-seq from 836 HNSCC patients (TCGA-HNSC n = 566, GSE65858 n = 270), single-cell RNA-seq (GSE139324, n = 26 patients, 133,308 cells), spatial transcriptomics (GSE208253, n = 12), proteomics (CPTAC-HNSCC, n = 108), and external validation cohorts (GSE41613, n = 97). CellChat ligand-receptor analysis, mediation analysis, Mendelian randomization (MR), LASSO-penalized Cox regression, HPV-stratified sensitivity analysis, and transcription factor (TF) correlation analysis were employed. Results: DSG2 exhibited epithelial-specific expression and showed consistent positive correlation with CXCL8 (IL-8; TCGA rho = 0.228, p = 4.4 & times; 10(-8)) and myCAF activation across independent cohorts. Single-cell analysis revealed that 99.5% of CXCL8-producing cells have zero DSG2 expression, establishing the bulk correlation as compositional rather than cell-intrinsic. CellChat identified CXCL8-CXCR2 as the strongest tumor-stroma interaction in DSG2-high regions (probability = 0.821, 1.80-fold enrichment). Mediation analysis demonstrated 43.6% (95% CI [34.3-53.6%]) of DSG2's tissue-level association with myCAF activation is mediated through CXCL8 (compositional mediation). Multi-instrument MR (IVW: Beta = -0.028, p = 0.028; I-2 = 0.0%) corroborated the compositional model. Protein-level validation in CPTAC-HNSCC confirmed DSG2-CD8A inverse correlation (Spearman rho = -0.35, p = 2.2 & times; 10(-4)). Pan-squamous meta-analysis confirmed negative DSG2-cytolytic activity correlations (pooled rho = -0.213, 95% CI [-0.296, -0.128], I-2 = 58.6%, 4 cohorts). DSG2 correlated with TIDE score (rho = 0.176) and TGF-beta exclusion subscore (rho = 0.428). DepMap analysis identified CXCR2 inhibitor collateral sensitivity (rho = -0.408, p < 0.0001). An eight-gene co-expression module was validated in two independent cohorts (GSE41613: HR = 3.09, p = 0.003; GSE65858: HR = 1.57, p = 0.032). Conclusions: DSG2 marks a stromal-immune organizational state characterized by CXCL8-CXCR2 paracrine signaling, myCAF activation, and immune exclusion, conserved across squamous malignancies. DSG2-high/PD-L1-high tumors (30.4% prevalence) exhibit the worst predicted ICI response and represent a candidate population for biomarker-selected CXCR2 inhibitor trials in combination with anti-PD-1 therapy.