Semaphorin 4D in human head and neck cancer tissue and peripheral blood: A dense fibrotic peri-tumoral stromal phenotype

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.

Semaphorin 4D is a potential biomarker in pediatric leukemia and promotes leukemogenesis by activating PI3K/AKT and ERK signaling pathways

“…Soluble Sema4D, which is released by proteolytic cleavage of the extracellular domain of transmembrane Sema4D, has been indicated to be involved in infectious and inflammatory diseases ( 2 ) and heart failure ( 50 ). The finding of high levels of soluble Sema4D in the plasma of patients with pediatric leukemia is consistent with results in human head and neck cancer ( 25 , 51 ), suggesting that Sema4D may be a potential biomarker for cancer diagnosis. Soluble Sema4D has also been reported to participate in cancer development by inducing metastasis ( 25 ), inhibiting differentiation ( 52 ) and suppressing the immune response ( 53 ).…”

Sja‐miR‐71a in Schistosome egg‐derived extracellular vesicles suppresses liver fibrosis caused by schistosomiasis via targeting semaphorin 4D

“…Studies have shown that Sema4D can directly increase TGF-β1; IL-13 and TGF-β1 were decreased in a Sema4D −/− mouse model of experimental asthma [31,32]. In addition, both TGF-β1/SMAD and IL-13/ STAT6 pathways have been identified as major pathways that promote liver fibrosis in schistosomiasis by activating HSCs [33,34,49].…”

“…Interestingly, Sema4D expression was down‐regulated in vitro and in vivo upon Sja‐miR‐71a overexpression. Sema4D binds with two receptors – Plexin B1 and CD72 [31]. In line with decreased Sema4D expression, both Plexin B1 and CD72 were down‐regulated after Sja‐miR‐71a treatment.…”

Semaphorins as emerging clinical biomarkers and therapeutic targets in cancer

“…Moreover, consistent with its activity promoting osteoclastogenesis and bone resorptive activity, the knock-down of Sema4D in HNSCC cells reduced bone invasion in preclinical mouse models. Sema4D secreted by cancer cells was also found to regulate the tumor microenvironment, promoting the recruitment from the bone marrow of myeloid-derived suppressor cells 78 , and the formation of a dense fibrotic peri-tumoral stroma 79 , both hindering anti-cancer immune response. Notably, Sema4D was detected in the plasma of head and neck cancer patients at significantly higher levels compared to healthy donors 79 .…”