The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

SIMPLE SUMMARY: Malignant phenotypes of head and neck squamous cell carcinomas (HNSCCs) are regulated by the pro- and anti-tumoral activities of immune modulatory cytokines associated with tumor microenvironments (TMEs). We first present the immune modulatory effects of pro-inflammatory cytokines, pro- and anti- (pro-/anti-) inflammatory cytokines, and anti-inflammatory cytokines upon HNSCC phenotypes. We then report our evaluation of the functions of cytokines and chemokines that mediate the crosstalk between tumors and stromal cells, including cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), plasmacytoid dendritic cells (pDCs), and tumor-associated macrophages (TAMs). In HNSCCs, the status of lymph node metastasis is an important hallmark of a worse prognosis. Several chemokines mediate lymph node metastases in HNSCC patients. There are therapeutic approaches, using antitumoral cytokines or immunotherapies, that target cytokines, chemokines, or signal molecules essential for the immune evasion of HNSCCs. Finally, modulation by human papilloma virus (HPV) infection in HNSCC phenotypes and the prognostic significance of serum cytokine levels in HNSCC patients are discussed. ABSTRACT: HNSCCs are the major progressive malignancy of the upper digestive and respiratory organs. Malignant phenotypes of HNSCCs are regulated by the pro- and anti-tumoral activities of the immune modulatory cytokines associated with TMEs, i.e., a representative pro-inflammatory cytokine, interferon (IFN)-γ, plays a role as an anti-tumor regulator against HNSCCs; however, IFN-γ also drives programmed death-ligand (PD-L) 1 expression to promote cancer stem cells. Interleukin (IL)-2 promotes the cytotoxic activity of T cells and natural killer cells; however, endogenous IL-2 can promote regulatory T cells (Tregs), resulting in the protection of HNSCCs. In this report, we first classified and mentioned the immune modulatory aspects of pro-inflammatory cytokines, pro-/anti-inflammatory cytokines, and anti-inflammatory cytokines upon HNSCC phenotypes. In the TME of HNSCCs, pro-tumoral immune modulation is mediated by stromal cells, including CAFs, MDSCs, pDCs, and TAMs. Therefore, we evaluated the functions of cytokines and chemokines that mediate the crosstalk between tumor cells and stromal cells. In HNSCCs, the status of lymph node metastasis is an important hallmark of a worse prognosis. We therefore evaluated the possibility of chemokines mediating lymph node metastases in HNSCC patients. We also mention therapeutic approaches using anti-tumoral cytokines or immunotherapies that target cytokines, chemokines, or signal molecules essential for the immune evasion of HNSCCs. We finally discuss modulation by HPV infection upon HNSCC phenotypes, as well as the prognostic significance of serum cytokine levels in HNSCC patients.