Immunomodulatory Effect

PSK activates both innate and adaptive immune systems in which inflammatory and immune cells are stimulated to proliferate and differentiate into effector cells via key pathways controlled by cytokines acting in an autocrine or paracrine manner (see (Fig.2).

Receptors for beta-glucan have been found on immune and inflammatory cells such as neutrophils8, natural killer cells9, monocyte/macrophage8,9, T and B cells10, suggesting that beta-glucan exerts its effect via a signalling pathway leading to the production of a variety of cellular immune functions through the release of soluble mediators including cytokines and chemokines.

In terms of effector function, several studies reported that PSK has the capacity to stimulate neutrophils and macrophages for enhanced cytotoxicity against tumour cells and to suppress lung metastasis in tumour-bearing mice and rats, probably through a TNF-a– dependent mechanism11,12.

PSK is also able to salvage and stimulate defective dendritic cells for enhanced T cell cytotoxicity against colon carcinoma cells in vitro13 and to induce NK cell cytotoxicity against NK-sensitive tumour cells via dependent and independent mechanisms involving IL-2 and PSK14. In addition, it can promote both phenotypic and functional maturation of dendritic cells derived from CD14+ human peripheral blood monocytes15, suggesting that it could be potentially useful in dendritic cell vaccine therapy.

It has been reported that PSK increased the production of circulating CD4+ T cells relative to CD8+ cells in cancer patients16,17 and restored delayed-type hypersensitivity (DTH) in patients as well as in tumour- bearing mice18 with defective cellular immunity. In addition, PSK has been reported to restore cellular immune function in older people without disease but who have depressed cellular immunity19,20. However, the response declined to pre-treatment levels when PSK was discontinued after taking PSK for 6-10 months.19,20 The reason for this is unclear but it does mean that the beneficial effect of PSK in individuals with depressed immunity is only sustainable when PSK is taken on a continual basis. Laboratory investigation showed no abnormalities in white blood cell count, ESR and liver function tests related to PSK.

Dendritic cells (DC) are potent antigen-presenting cells that induce anti-tumour immunity. However, a defective function of these cells can occur thus jeopardising the efficacy of DC-based immunotherapy in cancer patients. In vitro studies showed that PSK was capable of driving the maturation of dendritic cells to induce potent T cell cytotoxicity against tumour cells21.

>Cytotoxic T cells are activated by Th1 helper T cells associated with cellular immunity which is deficient in a cancer-bearing state due to a shift to a Th2 helper cell dominance associated with humoral immunity which is ineffective against tumour cells22.

Dendritic cells can be divided into DC1 and DC2 subpopulations which drive the differentiation of Th1 and Th2 cells, respectively. Therefore, maintaining a correct balance between the cellular (Th1/DC1) and humoral (Th2/DC2) immune responses is critical to host defence and survival as determined by the Th1 and Th2 patterns of cytokines produced. In patients who underwent surgical resection for gastric or colorectal cancer, oral PSK therapy resulted in a shift from a Th1/Th2 balance towards Th1 and DC1 dominance associated with anti-tumour activity22. Thus PSK treatment may suppress the induction of a Th2 shift associated with poor prognosis of cancer by promoting a Th1 dominance to enhance CTL cells induction, resulting in better outcome in patients with cancer22.

Orally administered PSK has been reported to stimulate immunomodulating cytokines such as IL-8 and TNF-a in peripheral blood mononuclear cells from normal healthy subjects as well as patients with gastric cancer23. Among cytokines produced in response to PSK in vitro, there are tumour-necrosis factors, TNF-a/b and IFN-g which are known to kill tumour cells and activate NK cell14 and T-cell cytotoxicity24,25 against tumour cell target, respectively. IL-8, a chemokine involved in chemotaxis is produced by neutrophils which play a key role in acute inflammatory response to bacterial infection, a normal process known to be crucial to host protection and disease resolution.

PSK is not only capable of stimulating the immune system but also modulating tumour cell function and the tissue environment to facilitate the local destruction of tumour cells by activated immune effector cells. For example, PSK was reported to suppress tumour-induced angiogenesis26, extravasation and metastasis26,27 and tumour invasiveness by inhibiting cytoskeletal functions and by down-regulating invasion-associated cytokines such as TGF-b, urokinase plasminogen activator (uPA), MMP-2 and MMP-9 and to augment infiltration of tumour-lymphokine activated killer cells (LAK)28,29. In addition, PSK is reported to act directly on tumour cells to enhance the expression of HLA-Class I antigen and adhesion molecule (ICAM-1) for increased containment and killing of tumour cells by effectors cells30.

A depressed immunity can be attributed to a number of causes including advanced age, stress, poor gut function due to disturbed microflora, infection, disease, exposure to carcinogens and treatment with immunosuppressive agents such as chemotherapy and radiation therapy commonly associated with immune suppression. For example, PSK may act as an anti-oxidant by enhancing superoxide dismutase (SOD) 31 and glutathione peroxidase activities to protect tissue damage from harmful effects of free radicals32-33, chemotherapy and/or radiotherapy34. PSK has been shown to delay or prevent cancer development in animals exposed to chemical carcinogens35. PSK is known to enhance cellular immunity associated with surgical stress36,37. Pre-treatment with PSK inhibited the decline in the numbers of CD4+ , cytotoxic T cells and NK cells and Con-A-induced T cell suppression caused by cyclophosphamide in patients undergoing radical surgery37,38 . In another study, PSK was shown to be effective in enhancing NK cell activity in subjects with chronic fatigue39.

PSK may also have potential benefits for the treatment of infectious diseases. Several studies have shown that PSK protects normal and immunosuppressed mice from infection with virus, fungi or bacteria normally associated with the effects of chemotherapy or radiotherapy7,40-41. PSK was found to interfere with the binding of HIV-1 virus to receptor on CD4+ T cells and to inhibit the activity of reverse transcriptase in culture42. Anti-viral activity was also demonstrated in type 1 and 2 strains of herpes simplex virus (HSV) by inhibiting protein synthesis43. The capacity of PSK to inhibit B cell growth infected with Epstein-Barr Virus (EBV) has recently being demonstrated44. It occurred via the activation of T cell function by monocytes producing IL-1544.

In tumour-bearing mice exposed to the effects of chemotherapy, PSK showed benefit by restoring normal intestinal microflora essential for healthy gut function45.

PSK can act directly on tumour cells through its ability to inhibit cancer spread46 and growth induced by angiogenesis26. Other direct anti-tumour effects of PSK included the ability to inhibit prostrate cancer cell sensitive to the hormone androgen47, indicating that PSK may be beneficial for treatment of patients with hormone-responsive prostrate cancer or as a maintenance therapy for patients with colorectal cancer following surgery48.

Fig. 2
Proposed Immunomodulatory and anti-tumour pathways of PSK