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Spatial Remodeling of the Immune Microenvironment During Laryngeal Carcinogenesis Reveals Prognostic Immune Patterns
Toni Vidović1,2, Filip Tudor1,2, Blažen Marijić1,2
1Department of Otorhinolaryngology, Head and Neck Surgery, Clinical Hospital Center Rijeka, 51000 Rijeka, Croatia.
Background/Objectives:
Despite therapeutic advances, laryngeal squamous cell carcinoma (LSCC) remains a clinical challenge. We investigated immune microenvironment remodeling and its prognostic relevance during laryngeal carcinogenesis.
Methods:
This retrospective study included 227 patients: 45 with benign laryngeal polyps, 55 with laryngeal epithelial dysplasia, and 127 with LSCC; 55 (43.3%) LSCCs were Union for International Cancer Control (UICC) stage I-II and 72 (56.7%) stage III-IV. Immunohistochemistry on tissue microarrays (TMAs) was used to assess the density of cluster of differentiation (CD)4-, CD8-, forkhead box P3 (FOXP3)-, programmed cell death protein 1 (PD-1)-, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)-, CD68-, and CD163-positive immune cells, together with FOXP3/CTLA-4 double-positive cells. Immune-cell densities were expressed as the percentage of the respective intraepithelial/intratumoral or stromal compartment occupied by positively stained immune cells. An exploratory Protective Immune Score (PIS; 0-2) assigned one point each for high intraepithelial FOXP3 and high stromal CTLA-4 cell density.
Results:
LSCC showed increased stromal immune-cell density and coordinated immune organization. Stromal PD-1 correlated with CD4, CD8, and FOXP3 density (rs = 0.561, 0.515, and 0.403), and stromal CTLA-4 with FOXP3 (rs = 0.556; all p < 0.0001). High intraepithelial FOXP3 was associated with improved disease-specific survival (DSS; hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.10-0.72) and disease-free survival (DFS; HR = 0.24, 95% CI 0.10-0.59). High stromal CTLA-4 similarly favored DSS (HR = 0.29, 95% CI 0.11-0.74) and DFS (HR = 0.26, 95% CI 0.11-0.61). The PIS remained independently associated with DSS (adjusted HR = 0.29, 95% CI 0.16-0.55) and DFS (adjusted HR = 0.29, 95% CI 0.17-0.52).
Conclusions:
Laryngeal carcinogenesis is characterized by progressive, compartment-specific immune remodeling, with the stroma emerging as the principal site of coordinated immune organization. The PIS captures spatially defined favorable immune features and warrants validation in independent cohorts.