Abstract
Background
A recent report showed that oral adjuvant immunochemotherapy with protein-bound polysaccharide K (PSK) and tegafur/uracil (UFT) for stage II and III colorectal cancer improves overall survival compared with UFT alone. PSK has been supposed to improve survival through immunological mechanisms such as induction of cytokines, regulation of Th1/Th2 balance, and inhibition of immunosuppressive molecules.
Methods
We investigated the mechanisms by which PSK influences immunological parameters such as Th1 cells (IFN-γ-positive CD4+ T cells), Th2 cells (IL-4-positive CD4+ T cells), Th1/Th2 ratio, NKT cells (CD56+ T cells and CD57+ T cells), NK cells, and CD25+CD4+ T cells in stage III gastric cancer patients. Patients were randomly assigned to receive either 3 g PSK plus 300 mg UFT (PSK group) or 300 mg UFT alone (control) orally each day for at least 1 year following their operation.
Results
Twenty-one registered patients with stage III gastric cancer were analyzed. The 3-year overall survival was 62.2% in the PSK group (n = 10) and 12.5% in the control group (n = 11) (P = 0.038). Before operation, there were no significant differences in the proportions of Th1 cells, Th2 cells, Th1/Th2 ratio, CD56+ T cells, CD57+ T cells, NK cells, and CD4+CD25+ T cells between PSK and control groups. However, after operation, CD57+ T cells decreased significantly in the PSK group compared to the control (P = 0.0486). When all patients were analyzed, patients with increased proportion (>18%) of CD57+ T cells showed worse survival than those with lower (≤18%) CD57+ T cells (3-year survival, 25.0 and 45.7%, respectively; P = 0.046), consistent with our previous report that high CD57+ is an indicator of poor prognosis in patients with advanced gastric cancer. However, in the group treated with PSK + UFT, 3-year survival of CD57-high patients was as great as that of CD57-low patients (66.7 and 51.4%, respectively; P = 0.67).
Conclusion
The present findings suggest that PSK improves overall survival of stage III gastric cancer patients partly by inhibiting CD57+ T cells, a proven poor prognostic factor in advanced gastric cancer.
Similar content being viewed by others
References
Tsukagoshi S, Hashimoto Y, Fujii G et al (1984) Krestin (PSK). Cancer Treat Rev 11:131–155
Kobayashi H, Matsunaga K, Oguchi Y (1995) Anti-metastatic effects of PSK (Krestin), a protein-bound polysaccharide obtained from basidiomycetes: an overview. Cancer Epidemiol Biomarkers Prev 4:275–281
Nakazato H, Koike A, Saji S et al (1994) Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Lancet 343:1122–1126
Mitomi T, Tsuchiya S, Iijima N et al (1992) Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. Dis Colon Rectum 35:123–130
Ohwada S, Ikeya T, Yokomori T et al (2004) Adjuvant immunochemotherapy with oral tegafur/uracil plus PSK in patients with stage II or III colorectal cancer: a randomized controlled study. Br J Cancer 90:1003–1010
Hirose K, Zachariae CO, Oppenheim JJ et al (1990) Induction of gene expression and production of immunomodulating cytokines by PSK in human peripheral blood mononuclear cells. Lymphokine Res 9:475–483
Abe Y, Miyake M, Horiuchi A et al (1990) Induction of cytokines by polysaccharide K in the peripheral blood mononuclear cell culture. J Clin Exp Med 152:617
Kanazawa M, Mori Y, Yoshihara K et al (2004) Effect of PSK on the maturation of dendritic cells derived from human peripheral blood monocyte. Immunol Lett 91:229–238
Harada M, Matsunaga K, Oguchi Y et al (1995) The involvement of transforming growth factor beta in the impaired antitumor T cell response at the gut-associated lymphoid tissue (GALT). Cancer Res 55:6146–6151
Van der Pouw Kraan TC, Beoije LC, Smeenk RJ et al (1995) Prostaglandin E2 is a potent inhibitor of human interleukin 12 production. J Exp Med 181:775–779
Matsuda JL, Gapin L, Fazilleau N et al (2001) Natural killer T cells reactive to a single glycolipid exhibit a highly diverse T cell receptor repertoire and small clone size. Proc Natl Acad Sci USA 98:12636–12641
Terabe M, Berzofsky JA (2008) The role of NKT cells in tumor immunity. Adv Cancer Res 101:277–348
Takii Y, Hashimoto S, Iiai T et al (1994) Increase in the proportion of granulated CD56+ T cells in patients with malignancy. Clin Exp Immunol 97:522–527
Okada T, Iiai T, Kawachi Y et al (1995) Origin of CD8+ CD57+ T cells which increase at tumour sites in patients with colorectal cancer. Clin Exp Immunol 102:159–166
Koyama S, Ebihara T, Fukao K (1992) Expression of intercellular adhesion molecule 1 (ICAM-1) during the development of invasion and/or metastasis of gastric carcinoma. J Cancer Res Clin Oncol 118:609–614
Karimine N, Nanbara S, Arinaga S et al (1994) Lymphokine-activated killer cell activity of peripheral blood, spleen, regional lymph node, and tumor infiltrating lymphocytes in gastric cancer patients. J Surg Oncol 55:179–185
Groux H, O’Garra A, Bigler M (1997) A CD4+ T cells subset inhibits antigen-specific T-cell responses and prevents colitis. Nature (Lond) 389:737–742
Thomason AM, Shevach EM (1998) CD4+ CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287–296
Thomason AM, Shevach EM (2000) Suppressor effector function of CD4+ 25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190
Takahashi T, Tagami T, Yamazaki S et al (2000) Immunologic self tolerance maintained by CD25+ CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–310
Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458
Shevach EM (2001) Certified professionals: CD4+ CD25+ suppressor T cells. J Exp Med 193:F41–F46
Azuma T, Takahashi T, Kinusato A et al (2003) Human CD4+ 25+ regulatory T cells suppress NKT cell functions. Cancer Res 63:4516–4520
Ichihara F, Kono K, Takahashi A et al (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patient with gastric and esophageal cancers. Clin Cancer Res 9:4404–4408
Wolf AM, Wolf D, Steurer M et al (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9:606–612
Sasada T, Kimura M, Yoshida Y et al (2003) CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer (Phila) 98:1089–1099
Picker LJ, Singh MK, Zdraveski Z et al (1995) Direct demonstration of cytokine synthesis heterogeneity among human memory/effector T cells by flow cytometry. Blood 86:1408–1419
Akagi J, Baba H (2008) Prognostic value of CD57+ T lymphocytes in the peripheral blood of advanced gastric cancer patients. Int J Clin Oncol (in press)
Oba K, Teramukai S, Kobayashi M et al (2007) Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer. Cancer Immunol Immunother 56:905–911
Wajchman HJ, Pierce CW, Varma VA et al (2004) Ex vivo expansion of CD8+CD56+ and CD8+CD56− natural killer T cells specific for MUC1 mucin. Cancer Res 64:1171–1180
Baxevanis CN, Gritzapis AD, Tsitsilois OE et al (2002) HER-2/neu-derived peptide epitopes are also recognized by cytotoxic CD3(+)CD56(+) (natural killer T) lymphocytes. Int J Cancer 20:864–872
Izquierdo M, Balboa MA, Fernandez-Ranada JM et al (1990) Relation between the increase of circulating CD3+CD57+ lymphocytes and T cell dysfunction in recipients of bone marrow transplantation. Clin Exp Immunol 82:145–150
Hilbe W, Eisterer W, Schmid C (1994) Bone marrow lymphocytes subsets in myelodysplastic syndromes. J Clin Pathol 47:505–507
Gorochov G, Debre P, Leblond V et al (1994) Oligoclonal expansion of CD8+CD8+CD57+ T cells with restricted T-cell receptor chain variability after bone marrow transplantation. Blood 83:587–595
Fregona I, Guttmann RD, Jean R (1985) HNK-1 + (Leu-7) and other lymphocyte subsets in long-term survivors with renal allotransplants. Transplantation 39:25–29
Arai K, Yamamura S, Seki S et al (1998) Increase of CD8+CD57+ T cells in knee joints and adjacent bone marrow of rheumatoid arthritis (RA) patients: implication for an anti-inflammatory role. Clin Exp Immunol 111:345–352
Dupuy d’Angeac A, Monier S et al (1993) Increased percentage of CD3+, CD57+ lymphocytes in patients with rheumatoid arthritis. Correlation with duration of disease. Arthritis Rheum 36:608–612
Legac E, Autran B, Merie-Beral H et al (1992) CD4+CD7–CD8+CD57+ T cells: a new T-lymphocyte subset expanded during human immunodeficiency virus infection. Blood 79:1746–1753
Sadat-Sowti B, Debre P, Mollet L et al (1994) An inhibitor of cytotoxic functions produced by CD8+ CD57+ T lymphocytes from patients suffering from AIDS and immunosuppressed bone marrow recipients. Eur J Immunol 24:2882–2888
Autran B, Leblond V, Sadat-Sowti B et al (1991) A soluble factor released by CD8+CD57+ lymphocytes from bone marrow transplanted patients inhibits cell-mediated cytolysis. Blood 77:2237–2241
Chochi K, Ichikura T, Majaima T et al (2003) The increase of CD8+CD57+ T cells in the peripheral blood and their impaired immune functions in patients with advanced gastric cancer. Oncol Rep 20:2443–2448
Characiejus D, Pasukoniene V, Kazlauskaite K et al (2002) Predictive value of CD8highCD57+ lymphocyte subset in interferon therapy of patients with renal cell carcinoma. Anticancer Res 22:3679–3684
Marinova E, Han S, Zheng B (2007) Germinal center helper T cells are dual functional regulatory cells with suppressive activity to conventional CD4+ T cells. J Immunol 178:5010–5017
Alvaro T, Lejeune M, Salvado MT et al (2006) Immunohistochemical patterns of reactive microenvironment are associated with clinicobiologic behavior in follicular lymphoma. J Clin Oncol 24:5350–5357
Mollet L, Sadat-Sowti B, Duntze J et al (1998) CD8hi+CD57+ T lymphocytes are enriched in antigen-specific T cells capable of down-modulating cytotoxic activity. Int Immunol 10:311–323
Frassanito MA, Silvestris F, Cafforio P et al (1998) CD8+/CD57 cells and apoptosis suppress T-cell functions in multiple myeloma. Br J Haematol 100:469–477
Sze DM, Giesajitis G, Brown RD et al (2001) Clonal cytotoxic T cells are expanded in myeloma and reside in the CD8 + CD57+CD28– compartment. Blood 98:2817–2827
Conflict of interest statement
No author has any conflict of interest.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Akagi, J., Baba, H. PSK may suppress CD57+ T cells to improve survival of advanced gastric cancer patients. Int J Clin Oncol 15, 145–152 (2010). https://doi.org/10.1007/s10147-010-0033-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10147-010-0033-1