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

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

Suppressive effect of mesenchymal stromal cells on interferon-γ-producing capability of spleen cells was specifically enhanced through humoral mediator(s) from mouse oral squamous cell carcinoma Sq-1979 Cells In Vitro

Aim: The aim of this study was to compare the immunomodulatory effects in the tumor milieu of mouse oral squamous cell carcinoma (OSCC) cells harboring primary and advanced phenotypes. We established an in vitro co-culture system using mouse OSCC cells, spleen cells, and mesenchymal stromal cells. Methods: Sq-1979 is an OSCC cell line derived from C3H mice; 233-11 cells were established from a primary Sq-1979 tumor; L3–5, L5–11, and L6–8 cells were established from lymph node-metastasized Sq-1979 cells. 10T1/2 is a fibroblast line derived from C3H mice. The OSCC cells were co-cultured with anti-CD3 antibody-stimulated mouse spleen cells in the presence or absence of 10T1/2 cells, and the producing capability of interferon (IFN)-γ and interleukin (IL)-10 was evaluated using enzyme-linked immunosorbent assay. Results: The production of IFN-γ by the stimulated spleen cells was specifically enhanced in the presence of co-cultured L-cells. The production of IL-10 was conversely reduced in the co-culture with all the OSCC cell lines used. The production of IFN-γ was significantly reduced in the co-culture with directly contacted 10T1/2 cells, and further reduction was observed in the presence of Sq-1979 and 233-11 cells but remained unchanged in the presence of L-cells. The reduction of IFN-γ production was also observed by the addition of conditioned medium from the Sq-1979-1 cells. Conclusion: Sq-1979 cells specifically enhanced the immune-suppressive activity of mesenchymal stromal cells through humoral factor (s)

The producing capabilities of Interferon-γ and Interleukin-10 of spleen cells in primary and metastasized oral squamous cell carcinoma cells-implanted mice

Aim: The aim of this study is to compare the immunomodulatory effects exerted by primary versus metastasized oral squamous cell carcinoma (OSCC) cells. Methods: Mouse OSCC cell line Sq-1979, 233 cells established from implanted Sq-1979 cells, and L cells established from the metastasized lymph node tissues of Sq-1979-implanted mice were subcutaneously inoculated into the later abdominal area of syngeneic C3H mice. The producing capabilities of interferon (IFN)-γ, a Th1 cytokine, and interleukin (IL)-10, a Th2 cytokine, by anti-CD3 antibody-stimulated spleen cells were investigated in tumor bearing-mice. Results: The quantity of IFN-γ produced by stimulated spleen cells was significantly suppressed in the mice implanted with Sq-1979, 233, and L cells. Conversely, the production of IL-10 was significantly elevated in Sq-1979 and 233 cell-implanted mice while markedly suppressed in L cell-implanted mice. Conclusion: Our results suggest that the metastasized L cells have acquired differential immunomodulatory functions compared to the original Sq-1979 and primary 233 cells