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.

Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ

“…HNSCCs demonstrate robust accumulation of MDSCs with immune suppressive capacity (9,15,37), but T reg s also contribute to immunosuppression within the HNSCC tumor microenvironment (10,38). Treg function appears to rely upon p110δ signaling(21).…”

Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells

“…Several cellular mediators of immunosuppression within the HNSCC TME have been identified, including myeloid derived suppressor cells (MDSCs) and regulatory T-lymphocytes (Tregs) [ 7 – 10 ]. MDSCs are likely recruited to the TME through chemokine signaling [ 11 , 12 ], expand locally in response to tumor cell secreted semaphorin 4D [ 13 ], and mediate suppression of T-lymphocyte function at least through STAT3-dependent production of arginase [ 14 ]. MDSCs can be divided into granulocytic or monocytic subtypes based on cell surface marker expression [ 15 ], and the relative abundance of each seems to vary amongst tumor types with both phenotypes expanded in patients with HNSCC [ 14 ].…”

Checkpoint Inhibition in Head and Neck Cancer: Immune Therapeutic Options, Limitations, and Beyond

“…It has been shown that MDSCs act via arginase I and inducible NO synthase, as well as via indoleamine 2,3-dioxygenase, IL-10, and TGF-β, to suppress T-cell functions [32] . In HNSCC, activation of STAT3 signaling as well as of tumor-derived semaphorin has been described [33,34] . Furthermore, the amount of MDSCs found in cancer patients correlates with poor prognosis and may counteract immune therapeutic approaches using checkpoint inhibitors [35,36] .…”