Inflammation substantially affects the risk of oral malignancy. Pro-inflammatory cytokine, interferon (IFN)-γ, confers anti-tumor activity using several different mechanisms. Conversely, higher expression of interleukin (IL)-17 is associated with worse prognosis. Monocyte chemotactic protein (MCP)-1 correlates positively with poor long-term survival of head and neck squamous cell carcinoma (HNSCC) patients. IL-1α affects cancer associated fibroblasts and macrophages, and promote several malignant phenotypes including immune suppression. Some anti-inflammatory cytokines, including IL-10 and transforming growth factor (TGF)-β, relate to pro-tumoral activities.Among immune checkpoint modulators, programmed death (PD-)1 and PD-ligand (L)1 facilitate oral squamous cell carcinoma (OSCC) cell evasion from immune surveillance, and the expression status of these has a prognostic value.OSCCs contain tumor associated macrophages (TAMs) as major stromal cells of their tumor microenvironment. Among the two distinctive states, M2 macrophages support tumor invasion, metastasis and immune suppression. Crosstalk between TAMs and OSCC or cancer-associated fibroblasts (CAF) plays an important role in the progression of OSCC.Clinical trials with blocking antibodies against IL-1α or melanoma-associated antigens have been reported as therapeutic approaches against OSCCs. The most promising approach activating antitumor immunity is the blockade of PD-1/PD-L1 axis. Manipulating the polarization of pro-tumorigenic macrophages has been reported as a novel therapeutic approach.

To evaluate systemic immunity associated with tumor growth limited to a subcutaneous site versus growth proceeding at multiple tumor sites, we established syngeneic mouse subcutaneous and pulmonary tumor models by local subcutaneous and intravenous injection of colon carcinoma CT26 cells. We found that splenic myeloid-derived suppressor cell (MDSC) levels were significantly increased in the subcutaneous tumor model but not in the pulmonary tumor model. Furthermore, both CD4+ and CD8+ T cells as well as CD4+ Foxp3+ T cells were significantly decreased in the subcutaneous tumor model and were largely unchanged in the pulmonary tumor model. In addition, the subcutaneous model, but not the pulmonary model, displayed a Th1 polarization bias. This bias was characterized by decreased IL-4, IL-9, and IL-10 production, whereas the pulmonary model displayed increased production of IL-10. These results suggest that the mode of tumor development has differential effects on systemic immunity that may, in turn, influence approaches to treatment of cancer patients.

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.

The mechanisms of immunomodulation by mesenchymal stromal cells remain poorly understood. In this study, the effects of mouse adipose tissue-derived mesenchymal stromal cells (ASCs) on mouse spleen cells alloreactively stimulated by anti-CD3 and anti-CD28 antibody-coated (anti-CD3/CD28) beads were observed. Production of interferon-γ by the anti-CD3/CD28 bead-stimulated spleen cells was significantly suppressed in co-culture with ASCs. However, an augmented intensity of CD69 on the stimulated spleen cells was not suppressed in the presence of ASCs. The immunosuppressive effects of ASCs were partially mediated by one or more soluble factors (26% suppression). However, the ASCs require cell-cell contact in order to maximally exert suppression (88%). The suppressive effect of ASCs mediated by direct cell contact was partially reversed following knockdown of β2 microglobulin, a component of the major histocompatibility complex (MHC) class I molecule, with siRNA. The results of the study demonstrated that ASCs have significant immune modulatory effects on alloreactively stimulated spleen cells. The effects of ASCs on spleen cells are dependent on soluble factor(s) and cell contact, which is mediated by the MHC class I complex on ASCs.

+ αβtcr + cells (cD57 + t cells), showed a significant inverse correlation with pB-IFn-γ-producing capability. the present results suggest that an increase in cD4 + cD57 + t cells controls the capability of pB to produce the antitumor cytokine IFn-γ and that pB-IFn-γ production is impaired with Hcc tumor progression. IntroductionHepatocellular carcinoma (HCC) is the fifth most common cancer in men and the eighth most common cancer in women worldwide. Hcc is highly prevalent in patients with chronic liver diseases resulting mainly from hepatitis B virus (HBV) or hepatitis c virus (HcV) infection, and its incidence is now increasing. In Japan, Hcc is the third most common cause of mortality, and the most frequent cause of Hcc is chronic infection with HcV (1,2 A b b re vi a t i o n s:A lt, a la n i n e t r a n s a m i n a s e; A F p, α

Introduction:In order to survive, cancers control immune systems and evade immune detection using mediators consisting of immune checkpoint molecules and cellular systems associated with immune suppression.Methodology:During the development of cancer and chronic infections, the immune checkpoints and cellular components including regulatory T cells, myeloid derived suppressor cells and cancer associated fibroblasts are often enhanced as a mechanism of immune subversion and have therefore become very important therapeutic targets.Conclusion:In this review, we will discuss the complexity of immune-suppressive mechanisms in the tumor milieu of cancers, including oral malignancy.

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Myeloid derived suppressor cells (MDSCs) localize to hematopoietic organs and peripheral blood during inflammation or tumor tissues and lymph nodes in the presence of a tumor. However, whether there are differences in MDSCs found in the primary tumor and metastases is unknown. In the present study, we established a cell line of metastasized tumor cells to a lymph node, L5-11, which were derived from the Sq-1979 mouse buccal mucosa squamous cell carcinoma cell line. We then analyzed tumor immunogenicity, especially with regard to MDSCs, to clarify the differences between the primary tumor and metastases, using an isogenic heterotopic tumor transplantation model. Our data showed that the population of intratumoral MDSCs, especially polymorphonuclear MDSCs in the lymph node metastasis model were significantly increased compared with syngeneic grafts from the primary cell line Sq-1979 after 21 days. Furthermore, we identified that the lymph node metastasis cell line had increased expression of genes that promote the expansion of MDSCs, tumor growth and metastasis. Hence, these data suggest that tumor immunosuppression can occur via activation of MDSCs. However, further examination is required to clarify whether all or a subset of these factors from the lymph node metastasis tumor cells are required to induce intratumoral MDSCs.