Therefore, the relationship between the expression of CD40 and tumor growth may be related to tumor types (61, 62). So far, CD40 agonist antibodies (SGN-40, CP-870,893) are being tested in early clinical trials either alone or in combination with mAbs for lymphoma and solid tumors in humans (63). However, some studies showed that OX40-stimulated Tregs by agonist mAbs retained suppressive qualities, and Tregs function had not intrinsically been impaired. The expression of IFN-, TNF-, and granzyme B, which had potent anti-tumor effects, was increased significantly, and this may provide another explanation for the mechanism of OX40 (37). OX40 could be expressed on the surface of T cells in HNSCC patients (38). Recent studies have found that the expression of OX40 on CD4(+) T cell surfaces in HNSCC patients was lower than in healthy people. Compared to patients with early tumors, the level of OX40 expressed on the CD4+ T cell surface was significantly decreased in patients with advanced tumors (39). In HNSCC, the low expression of OX40L could not help secrete adequate cytokines with anti-tumor effects (40). A series of pre-clinical experiments have shown that anti-OX40 dose-tolerant mAb could enhance the humoral and cellular immunity of cancer patients by amplifying the effector T cells and inhibiting the function of Tregs (41, 42). In a mouse ovarian tumor, the combined application of anti-PD-1/OX40 mAb had greatly improved the anti-tumor effect (43). Besides, Gough, et al. showed that, in tumor animal models, the overall survival could be effectively improved from 50% to 100% by combining anti-OX40 therapies after complete surgery or radiotherapy (44). It indicated that OX-40 mAbs could play a Xanthinol Nicotinate synergistic role with traditional treatment (45), which provided a new promising combination treatment for HNSCC patients. HIF1A CD40 CD40 is a costimulatory receptor molecule on the surface of APCs (DCs), monocytes and tumor cells. CD154, the ligand of CD40, is generally expressed on the surface of T cells and some innate immune cells, such as activated DCs and NK cells (46). Circulating sCD40L was higher in tumor patients, which may have a predictive role and could be an ambiguous therapeutic target (47). Binding with its ligand CD154, CD40 without enzymatic Xanthinol Nicotinate activity in the cytoplasmic domain recruits and interacts with TNF-receptor-associated factors (TRAFs), promoting the activation of the NF-B signaling to maintain homeostasis and immunogenic pathogenic processes (48, 49). The activation of the CD40/CD154 axis results in the secretion of cytokine, transformation of immunoglobulin gene, prevention of B-cell apoptosis, increased expression of costimulatory molecules such as CD80 and CD86, formation of germinal center, production of high-affinity antibodies and formation of B memory cells (50). Furthermore, a combination of CD40/CD154 could promote antigen presentation, help effector T cells exert their role, activate mononuclear cells and down-regulate the expression of inhibitory molecules, such as PD-1 (15). Stimulated CD40 could play a direct role in killing tumor cells Xanthinol Nicotinate (51). CD40 agonists promoted the secretion of lL-12 and reduced the expression of PD-1 on the surface of CD8+ T cells (52). Besides, anti-CD40 mAb treatment reversed phenotypic T cell exhaustion and increased the sensitivity of mAbs Xanthinol Nicotinate against anti-PD1 refractory tumors (53). In mouse tumor models, high expression of CD40/CD154 had an anti-tumor effect, and a low level of CD40/CD154 was shown to promote tumor growth. A possible explanation for this was that the former was related to IL-12, while the latter was associated with IL-10 (54C56). As for HNSCC patients with tumor high stage, the expression of CD40 on APCs as well as tumor cells Xanthinol Nicotinate decreased, and the same applies the level of CD154 on.