Abstract 3672: Semaphorin 4D in human head & neck cancer: A promising predictive biomarker for the peri-tumoral stromal phenotype
Authors: Rania H. Younis, Roshanak Derakhshandeh, Ahmed Sultan, Haiyan Chen, Kyu Lee Han, Tonya J. Webb
Journal: Cancer Research (2017)

Abstract Semaphorin 4D in human head and neck cancer: A promising predictive biomarker for the peri-tumoral stromal phenotype The search for biomarkers that can predict the tumor stromal phenotype in cancer patients is a challenge in the field. Semaphorin 4D (Sema4D), known for its various effects in the nervous, vascular and immune system, plays an important role in regulating pro and anti-inflammatory responses. It is over-expressed in Head and Neck cancer (HNC) as well as in other epithelial malignancies. We have recently described that HNC-associated Sema4D modulates the inflammatory profile to an immune-suppressive phenotype by inducing the expansion of myeloid derived suppressor cells. The purpose of this study was to determine the prognostic value of Sema4D as a biomarker for immune suppression in human HNC tissue and sera. Immunohistochemistry showed Sema4D+ve/high tumors to correlate positively with Stage III disease (p=0.014), and nodal metastasis (p=0.117). Sema4D+ve/high tumors correlated directly with dense fibrotic peri-tumoral stroma (p=0.0001) and inversely with tumor-associated inflammatory cells (TAIs) (p=0.0006). Knockdown of Sema4D in HNC cell lines resulted in significant reduction of TGF-β1 production (p=0.0016). Sema4D+ve/high tumor cells inversely correlated with the programmed death ligand 1 (PDL-1) positive tumors. Finally, Sema4D was detected in sera of HNC patients at higher levels compared to healthy donors (p &amp;lt;0.0001). In conclusion, we present a novel Sema4D+ve/high HNC tumor phenotype; with dense fibrotic peri-tumoral stroma. We also present Sema4D as a diagnostic biomarker in sera of HNC patients that can also be a promising predictor of the tumor stromal phenotype. This is of clinical interest as a predictive biomarker and a promising target for co-inhibition to sensitize patients for standard immunotherapy. [1-4] References: 1. Younis RH, Han KL and Webb TJ. Human Head and Neck Squamous Cell Carcinoma-Associated Semaphorin 4D Induces Expansion of Myeloid-Derived Suppressor Cells. J Immunol. 2016; 196(3):1419-1429. 2. Basile JR, Castilho RM, Williams VP and Gutkind JS. Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci U S A. 2006; 103(24):9017-9022. 3. Gajewski TF. The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment. Semin Oncol. 2015; 42(4):663-671. 4. Fisher TL, Reilly CA, Winter LA, Pandina T, Jonason A, Scrivens M, Balch L, Bussler H, Torno S, Seils J, Mueller L, Huang H, Klimatcheva E, Howell A, Kirk R, Evans E, et al. Generation and preclinical characterization of an antibody specific for SEMA4D. MAbs. 2016; 8(1):150-162. Citation Format: Rania H. Younis, Roshanak Derakhshandeh, Ahmed Sultan, Haiyan Chen, Kyu Lee Han, Tonya J. Webb. Semaphorin 4D in human head &amp; neck cancer: A promising predictive biomarker for the peri-tumoral stromal phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3672. doi:10.1158/1538-7445.AM2017-3672