Correlation between efficacy of PSK postoperative adjuvant immunochemotherapy for gastric cancer and expression of MHC class I

Abstract

Abstract. Protein-bound polysaccharide K (PSK) is a glycoprotein that is purified from the mushroom Coriolus versicolor. In Japan, PSK is clinically used in combination with anticancer agents following gastric cancer surgery. Evaluation of the response is difficult, as efficacy is determined via antitumor immunoenhancing effects, and for that reason PSK has not become a standard therapy. The present study evaluated the expression of MHC class I in gastric cancer patients who received PSK postoperative adjuvant immunochemotherapy, and investigated the correlation between MHC class I expression and clinical outcomes. The subjects comprised 349 patients with stage II/III gastric cancer, who had received adjuvant therapy following curative resection between 1995 and 2008. MHC class I expression in the primary lesion was evaluated by immunohistochemical staining. Patients were divided into two treatment groups: one was only administered oral chemotherapy (chemotherapy-only group) and the other was administered chemotherapy plus PSK (PSK group). The clinical outcomes were compared between the two groups. The two groups did not differ in regard to their MHC class I expression. Expression-negative cases demonstrated 3-year recurrence-free survival (RFS) rates of 65% in the PSK group and 47% in the chemotherapy-only group. Therefore, the PSK group revealed a prolonged survival. For the 82 expressionnegative cases with pN2 or greater, the RFS rates were 68% in the PSK group and 28% in the chemotherapy-only group, representing a significant difference. Thus, PSK adjuvant immunochemotherapy may be effective in MHC class I-negative patients, who are in a state of antitumor immunological tolerance, and patients with advanced lymph node metastasis of pN2 or greater. IntroductionIn Japan, adjuvant therapy using S-1 is considered effective for stage II/III gastric cancer. However, postoperative recurrence is observed in 30% of stage III patients, and the efficacy of S-1 monotherapy is marginal (1). Thus, combination of S-1 with various anticancer agents is being tested. Protein-bound polysaccharide K (PSK) is a glycoprotein extracted from the mushroom Coriolus versicolor belonging to the Polyporaceae family (2). Use of this antitumor agent is approved by the Japanese health insurance system, and has been confirmed to prolong survival in gastric cancer patients. PSK is considered to demonstrate not only direct cytocidal activity, but also antitumor immunoenhancing effects (3,4). However, the mechanisms of these effects remain unclear, and in addition, since 1994 no studies have reported any clinical efficacy of PSK against gastric cancer, thus this agent has not been recognized as a standard therapy (5).The fact that hosts become immunocompromised at the time of tumor progression has long been considered to be significant. In particular, decreased expression of MHC class I by the tumor is one mechanism which allows evasion of cytotoxic T lymphocytes (CTLs), which play a central role in tumor immunity (6). This has been reported t...

Medicinal Mushrooms: Bioactive Compounds, Use, and Clinical Trials

“…It increased dendritic cells (DC)s and CD4+ and CD8+ T cells, decreased B cells, induced the secretion of Th1 cytokines and IL-2, increased IFN-γ levels, and promoted DC maturation (CD86+ MHCII; higher levels of IL-12p40 and IL-12p70 were recorded, as was the inhibition of tumor growth. Other research has reported similar results, such as the activation of cytotoxic T cells (TC cells), improved DC maturation, the increased production of IL-8 and other cytokines (TNF-α, IL-1, IL-4, IL-6, IFN-γ) through the activation of T cell receptors (TCRs), enhanced major histocompatibility complex (MHC) class I expression by tumor cells, the inhibition of tumor growth, and the in vitro reduction of tumor growth factor-β (TGF-β) [ 16 , 17 , 18 ]. Thus, PSK can strengthen the body’s natural immune response.…”

“…Glycoprotein PSK was evaluated by Ito et al [ 18 ] for its possible influence on the expression of major histocompatibility complex (MHC) class I expression in advanced gastric cancer patients after surgery. They compared two groups of subjects, one receiving only chemotherapy and the other immunochemotherapy with 3 g/day PSK for 19 months, in a total of 349 individuals.…”

Purification, characterization, and antitumor activity of a novel glucan from the fruiting bodies of Coriolus Versicolor

“…The medium component also affects the M W of the polysaccharide [ 8 ]. Both products Polysaccharopeptide (PSP), and Protein-bound polysaccharide-K (PSK) have a molar mass of approximately 100 kDa [ 12 ]. The extracellular polysaccharide (EPS) contains small amounts of galactose, mannose, arabinose, xylose and predominantly glucose.…”

“…Several research papers have also revealed that the mechanism of D- β-1,3-D-glucans is due to their triple helix conformation as their tertiary structure [ 9 , 10 ]. PSK on the other hand, can modulate the expression of major histocompatibility complex (MHC) classI, inhibit NF-<kappa>B activation, downregulate the antiapoptotic molecules cIAP-1 and leads to activation of caspase-3 resulting in apoptosis of cancer cells, induce production of interleukin 8 by reacting with circulating monocytes, and also activates CTLs and maturation of dendritic cells [ 11 , 12 ]. CVPs-B can inhibit proliferation and enhance apoptosis of Eca109 cells; inhibit the expression of the osteopontin (OPN) gene; down-regulate glycosaminoglycan (GAG) expression on the surface of macrophages; affect the expression of inflammatory chemotactic factor; and enable the cells proceed rapidly to the resting phase of cell growth [ 13 ].…”

Phytochemicals for the Prevention and Treatment of Gastric Cancer: Effects and Mechanisms

“…In a multi-institutional randomized prospective study, combined with clinical medicine tegafur and cisplatin, lentinan could prolong median survival and improve the quality of life in patients with gastric cancer [125]. In addition, a clinical study including 349 subjects with stage II/III gastric cancer revealed that adjuvant treatment of protein-bound polysaccharide K from the mushroom Coriolus versicolor could prolong the survival of major histocompatibility complex (MHC) class I-negative patients [126]. Generally, several natural products exhibited significant synergistic effects with anticancer drugs against gastric cancer.…”