title: Human Head and Neck Squamous Cell Carcinoma-Associated Semaphorin 4D Induces Expansion of Myeloid-Derived Suppressor Cells.
abstract: One of the mechanisms by which malignancies can induce immune suppression is through the production of cytokines that affect the maturation and differentiation of inflammatory cells in the tumor microenvironment. Semaphorin 4D (Sema4D) is a proangiogenic cytokine produced by several malignancies, which has been described in the regulation of the immune system. In the present study, we examined the role of human head and neck squamous cell carcinoma (HNSCC)-secreted Sema4D on myeloid cell differentiation. CD33(+) cells cultured in HNSCC cell line-derived conditioned medium differentiated into myeloid derived suppressor cells (MDSC) (CD33(+)CD11b(+)HLA-DR(-/low)). The addition of anti-Sema4D Ab to HNSCC conditioned medium significantly reduced the expansion of the MDSC population. Similarly, knockdown of Sema4D in an HNSCC cell line resulted in a loss of MDSC function as shown by a decrease in the production of the immune-suppressive cytokines arginase-1, TGF-β, and IL-10 by MDSC, concomitant with recovery of T cell proliferation and IFN-γ production following stimulation of CD3/CD28. Importantly, CD33(+) myeloid and T cells cultured in conditioned medium of HNSCC cells in which Sema4D was knocked down promoted antitumor inflammatory profile, through recovery of the effector T cells (CD4(+)T-bet(+) and CD8(+)T-bet(+)), as well as a decrease in regulatory T cells (CD4(+)CD25(+)FOXP3(+)). We also showed that Sema4D was comparable to GM-CSF in its induction of MDSC. Collectively, this study describes a novel immunosuppressive role for Sema4D in HNSCC through induction of MDSC, and it highlights Sema4D as a therapeutic target for future studies to enhance the antitumorigenic inflammatory response in HNSCC and other epithelial malignancies.
authors.affiliation: Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Baltimore, MD 21201; Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Baltimore, MD 21201; and ryounis@umaryland.edu.
authors.forename: Rania H
authors.initials: RH
authors.lastname: Younis
authors.affiliation: Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Baltimore, MD 21201;
authors.forename: Kyu Lee
authors.initials: KL
authors.lastname: Han
authors.affiliation: Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Baltimore, MD 21201; and Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, MD 21201.
authors.forename: Tonya J
authors.initials: TJ
authors.lastname: Webb
mesh_terms: D015703:Antigens, CD / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006258:Head and Neck Neoplasms / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D015151:Immunoblotting; D008213:Lymphocyte Activation / Q000276:immunology; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D034741:RNA, Small Interfering; D039961:Semaphorins / Q000276:immunology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014162:Transfection; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D015703:Antigens, CD; C093224:CD100 antigen; D034741:RNA, Small Interfering; D039961:Semaphorins