Abstract
The search for stromal biomarkers in carcinoma patients is a challenge in the field. Semaphorin 4D (Sema4D), known for its various developmental, physiological and pathological effects, plays a role in pro and anti-inflammatory responses. It is expressed in many epithelial tumors including head and neck squamous cell carcinoma (HNSCC). Recently, we found that HNSCC-associated Sema4D modulates an immune-suppressive, tumor-permissible environment by inducing the expansion of myeloid derived suppressor cells. The purpose of this study was to determine the value of Sema4D as a biomarker for the peri-tumoral stromal phenotype in human HNSCC. Our data showed Sema4D+ve/high tumor cells in 34% of the studied cohort with positive correlation to Stage III (p=0.0001). Sema4D+ve/high tumor cells correlated directly with dense fibrotic peri-tumoral stroma (p=0.0001) and inversely with infiltrate of Sema4D+ve/high tumor-associated inflammatory cells (TAIs) (p=0.01). Most of the Sema4D+ve/high TAIs were co-positive for the macrophage biomarker CD163. Knockdown of Sema4D in WSU-HN6 cells inhibited collagen production by fibroblasts, and decreased activated TGF-β1 levels in culture medium of HNSCC cell lines. In a stratification model of HNSCC using combined Sema4D and the programmed death ligand 1 (PDL-1), Sema4D+ve/high tumor cells represented a phenotype distinct from the PDL-1 positive tumors. Finally,Sema4D was detected in plasma of HNC patients at significantly higher levels (115.44, ± 39.37) compared to healthy donors (38.60± 12.73) (p <0.0001). In conclusion, we present a novel HNSCC tumor stratification model, based on the expression of the biomarker Sema4D. This model opens new avenues to novel targeted therapeutic strategies.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide
We investigated the immunohistochemical expression of Semaphorin 4D (Sema4D) by head and neck squamous cell carcinoma (HNSCC) tumor cells in correlation to clinical parameters and the peri-tumoral stromal phenotype
We showed that high levels of Sema4D expression (Sema4D+ve/high) by HNSCC tumor cells significantly correlated with clinical staging, being highest in stage III
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. In the US alone, 61,760 new cases and 13,190 deaths were expected to occur in the year 2016 [1]. Patients can suffer multiple primaries or recurrences with a 6 months average survival rate for advanced cases [2,3,4]. Tumor cell interaction within the microenvironment and their modulation of angiogenic factors, inflammation and fibrosis in the peri-tumoral stroma is essential for tumor progression [5,6,7]. Understanding the mechanisms that influence tumor inflammation and how to utilize the inflammatory mediators as readers that can predict the peri-tumoral stromal phenotype and patients’ differential response to several therapeutic modalities is essential [8, 9]
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