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2018 ; 9
(13
): 11126-11144
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Semaphorin 4D in human head and neck cancer tissue and peripheral blood: A dense
fibrotic peri-tumoral stromal phenotype
#MMPMID29541402
Derakhshandeh R
; Sanadhya S
; Lee Han K
; Chen H
; Goloubeva O
; Webb TJ
; Younis RH
Oncotarget
2018[Feb]; 9
(13
): 11126-11144
PMID29541402
show ga
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-?1 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.
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