Therefore, the relationship between the expression of CD40 and tumor growth may be related to tumor types (61, 62)

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.

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