Hypoxia-induced stromal and immune remodeling in gastric carcinoma: correlation of Hypoxia-inducible factor 1-alpha (HIF-1α) expression with cancer-associated fibroblast (CAF) subtypes and Programmed death-ligand 1 (PD-L1) expression
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Background
Gastric carcinoma remains a major cause of cancer-related mortality worldwide, with tumor progression increasingly recognized as a consequence of complex interactions within the tumor microenvironment. Hypoxia-induced signaling, cancer-associated fibroblast (CAF) heterogeneity, and immune checkpoint activation play critical roles in tumor progression and immune evasion. However, their integrated relationship in gastric carcinoma remains insufficiently characterized.
Objectives
To evaluate the expression of Hypoxia-inducible factor 1-alpha and its association with cancer-associated fibroblast subtypes and Programmed death-ligand 1 expression in gastric carcinoma.
Methods
This cross-sectional analytical study included 100 histologically confirmed gastric carcinoma cases from Satkhira Medical College. Immunohistochemistry was performed for HIF-1α, α-smooth muscle actin (α-SMA), interleukin-6/fibroblast activation protein (IL-6/FAP), and PD-L1. CAFs were subclassified into myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs). Associations between biomarkers and clinicopathological variables were analyzed using chi-square test, Spearman correlation, and multivariate logistic regression. Receiver operating characteristic (ROC) curve analysis was used to assess model performance.
Result
High HIF-1α expression was observed in 55% of cases and demonstrated significant association with poor differentiation (p = 0.001), advanced tumor stage (p = 0.002), and lymph node metastasis (p = 0.001). iCAF predominance was significantly associated with poor differentiation (p = 0.003), advanced stage (p = 0.004), and nodal metastasis (p = 0.004). High PD-L1 expression was significantly associated with poor differentiation (p = 0.03), advanced stage (p = 0.001), and lymph node metastasis (p = 0.002). Multivariate logistic regression identified high HIF-1α expression (OR = 3.8, p = 0.001), iCAF dominance (OR = 4.5, p < 0.001), and advanced tumor stage (OR = 2.9, p = 0.004) as independent predictors of high PD-L1 expression. Combined high HIF-1α expression and CAF activation demonstrated the highest rate of PD-L1 positivity (76.7%, p < 0.001). ROC curve analysis demonstrated good predictive performance of the model with an area under the curve of 0.81.
Conclusion
The present study demonstrates a significant interaction between hypoxia, stromal remodeling, and immune checkpoint activation in gastric carcinoma. High HIF-1α expression and inflammatory CAF predominance are strongly associated with aggressive clinicopathological features and increased PD-L1 expression, supporting the existence of a coordinated hypoxia–stroma–immune axis in gastric carcinoma progression. These findings may have potential implications for prognostic stratification and combined targeted therapeutic strategies.
