Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1994 Apr;85(4):409–417. doi: 10.1111/j.1349-7006.1994.tb02374.x

Reconstitution of Anti‐tumor Effects of Lentinan in Nude Mice: Roles of Delayed‐type Hypersensitivity Reaction Triggered by CD4‐positive T Cell Clone in the Infiltration of Effector Cells into Tumor

Manabu Suzuki 1,✉, Michihiro Iwashiro 2, Fumihiko Takatsuki 1, Kagemasa Kuribayashi 2, Junji Hamuro 1
PMCID: PMC5919478  PMID: 7911123

Abstract

Lentinan, an antitumor polysaccharide used clinically in Japan, requires the intact T cell compartment to manifest its antitumor effects. The aim of the current study was to clarify the mechanisms playing crucial roles in the T cell requirement in the expression of antitumor effects of lentinan. Lentinan treatment of BDF1 mice transplanted intradermally with FBL‐3 induced complete tumor regression and a marked increase in survival time. The antitumor action of lentinan was abolished in mice treated simultaneously with antibodies to CD4 and CD8 antigens, whereas antibody to CD4, CD8 or NK1.1 alone was ineffective. The natural killer, cytotoxic T lymphocyte, and helper T cell activities were already augmented in this FBL‐3/BDF1 system and thus further augmentation of these activities by lentinan was not observed. These activities did not correlate with the antitumor activity of lentinan, as was confirmed in lymphocyte subset depletion experiments. On the contrary, the delayed‐type hypersensitivity (DTH) response against tumor‐associated antigens was triggered by lentinan and was abrogated only in mice treated simultaneously with antibodies to CD4 and CD8 antigens. Furthermore, a non‐cytolytic tumor‐associated antigen‐specific CD4+ T cell clone able to induce the DTH response in concert with lentinan reconstituted the antitumor effects in B6 nude mice when administered with lentinan. These results suggest that, in addition to the augmentation of immune effector cell activity against tumors, infiltration of these cells into the tumor burden initiated by the DTH responses at tumor sites may be involved in eradication of tumors by lentinan.

Keywords: Lentinan, Antitumor effect, DTH, CD4 T cell clone, Effector infiltration

Full Text

The Full Text of this article is available as a PDF (554.8 KB).

REFERENCES

  • 1. ) Heidelberger , C.Chemical oncogenesis in culture . Adv. Cancer Res. , 18 , 317 – 366 ( 1973. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Fujimoto , S. , Green , M. I. and Sehon , A. H.Regulation of the immune response to tumor antigens. I. Immunosuppressor cells in tumor‐bearing hosts . J. Immunol. , 116 , 791 – 799 ( 1976. ). [PubMed] [Google Scholar]
  • 3. ) Old , L. C.Cancer immunology . Sci. Am. , 237 , 62 – 79 ( 1977. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Dye , E. S. and North , R. J.T cell‐mediated immunosuppression as an obstacle to adoptive immunotherapy of the P815 mastocytoma and its metastases . J. Exp. Med. , 154 , 1033 – 1041 ( 1981. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Hosakawa , M. , Sawamura , Y. , Morikage , T. , Okada , F. , Xu , Z. Y. , Morikawa , K. , Itoh , J. and Kobayashi , H.Improved therapeutic effects of interleukin 2 after the accumulation of lymphokine‐activated killed cells in tumor tissue of mice previously treated with cyclophosphamide . Cancer Immunol. Immunother. , 26 , 250 – 256 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Lotze , M. T. , Line , B. R. , Mathisen , D. J. and Rosenberg , S. T.The in vivo distribution of autologous human and murine lymphoid cells grown in T cell growth factor (TCGF): implications for the adoptive immunotherapy of tumors . J. Immunol. , 125 , 1487 – 1493 ( 1980. ). [PubMed] [Google Scholar]
  • 7. ) Trial , J.Cooperation between early acting delayed‐hypersensitivity T‐cell and cultured cells in tumor rejection . Cancer Res. , 48 , 5922 – 5926 ( 1988. ). [PubMed] [Google Scholar]
  • 8. ) Hamuro , J. and Chihara , G.Lentinan, a T‐cell‐oriented immunopotentiator: its experimental and clinical applications and possible mechanism of immune modulation . In “ Immune Modulation Agents and Their Mechanisms ,” ed. Feniche R. L. , pp. 409 – 435 ( 1085. ). Marcel Dekker Inc. , New York . [Google Scholar]
  • 9. ) Suga , T. , Shiio , T. , Maeda , Y. and Chihara , G.Antitumor activity of lentinan in murine syngeneic and autochthonous hosts and its suppressive effects on 3‐methyl‐cholanthrene‐induced carcinogenesis . Cancer Res. , 44 , 5132 – 5137 ( 1984. ). [PubMed] [Google Scholar]
  • 10. ) Maeda , Y. and Chihara , G.The effects of neonatal thymectomy on the antitumor activity of lentinan, carboxymethylpachymaran and zymosan, and their effects on various immune responses . Int. J. Cancer , 8 , 41 – 46 ( 1973. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Suzuki , M. , Higuchi , S. , Taki , Y. , Taki , S. , Miwa , K. and Hamuro , J.Induction of endogenous lymphokine‐activated killer activity by combined administration of lentinan and interleukin 2 . Int. J. Immunopharm. , 12 , 613 – 619 ( 1990. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Masuko , Y. , Nakajima , H. , Tsubouchi , J. , Yamazaki , M. , Mizuno , D. and Abe , S.Changes of antitumor immunity of hosts with murine mammary tumors regressed by lentinan: potentiation of antitumor delayed hypersensitivity reaction . Gann , 73 , 790 – 797 ( 1982. ). [PubMed] [Google Scholar]
  • 13. ) Iwashiro , M. , Kondo , T. , Shimizu , T. , Yamagishi , H. , Takahashi , K. , Matsubayashi , Y. , Masuda , T. , Otaka , A. , Fujii , N. , Ishimoto , A. , Miyazawa , M. , Robertson , M. N. , Chesebro , B. and Kuribayashi , K.Multiplicity of virus‐encoded helper T‐cell epitopes expressed on FBL‐3 tumor cells . J. Virol. , 67 , 4533 – 4542 ( 1993. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. ) Sasaki , T. and Takasuka , N.Further study of the structure of lentinan, an antitumor polysaccharide from Lentinus edodes . Carbohydrate Res. , 47 , 99 – 104 ( 1976. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Dialynas , D. P. , Quan , Z. S. , Wall , K. A. , Pires , A. , Quintous , J. , Loken , M. R. , Pierres , M. and Fitch , F. W.Characterization of the murine T call surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu3/T4 molecule . J. Immunol. , 131 , 2445 – 2451 ( 1983. ). [PubMed] [Google Scholar]
  • 16. ) Nakayama , E. and Uenaka , A.Effects of in vivo administration of Lyt antibodies. Lyt phenotype of T cells in lymphoid tissues and blocking of tumor rejection . J. Exp. Med. , 161 , 345 – 355 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Koo , G. C. , Dumont , F. J. , Tutt , M. , Hackett , J. and Kumar , V.The NK1.1(—)mouse: a model to study differentiation of murine NK cells . J. Immunol. , 137 , 3742 – 3747 ( 1986. ). [PubMed] [Google Scholar]
  • 18. ) Greenberg , P. D. , Kern , D. E. and Cheever , M. A.Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt‐1+2− T cells; tumor eradication does not require participation of cytotoxic T cells . J. Exp. Med. , 161 , 1122 – 1134 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Mills , C. D. and North , R. J.Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipients: inhibition by suppressor T cells . J. Exp. Med. , 157 , 1448 – 1460 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. ) Shu , S. , Chou , T. and Rosenberg , S. A.Generation from tumor‐bearing mice of lymphocytes with in vivo therapeutic efficacy . J. Immunol. , 139 , 295 – 304 ( 1987. ). [PubMed] [Google Scholar]
  • 21. ) Fujiwara , H. , Hamaoka , T. , Shearer , G. M. , Yamamoto , H. and Terry , W. D.The augmentation of in vivo tumor‐specific T cell‐mediated immunity by amplifier T lymphocytes . J. Immunol. , 124 , 863 – 869 ( 1980. ). [PubMed] [Google Scholar]
  • 22. ) Fujiwara , H. , Fukuzawa , M. , Yoshioka , T. , Nakajima , H. and Hamaoka , T.The role of tumor‐specific Lyt‐1+2− T cells in eradicating tumor cells in vivo. I. Lyt‐1+2− T cells do not necessarily require recruitment of host's cytotoxic T cell precursors for implementation of in vivo immunity . J Immunol. , 133 , 1671 – 1676 ( 1984. ). [PubMed] [Google Scholar]
  • 23. ) Mowat , A. M. , Borland , A. and Parrott , D. M.Augmentation of natural killer cell activity by anti‐host delayed‐type hypersensitivity during the graft‐versus‐host reaction in mice . Scand. J. Immunol. , 22 , 389 – 399 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 24. ) Golding , H. T. , Munitz , T. I. and Singer , A.Characterization of antigen‐specific, Ia‐restricted, L3T4+ cytolytic T lymphocytes and assessment of thymic influence on their self specificity . J. Exp. Med. , 162 , 943 – 961 ( 1985. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. ) Greenberg , P. D.Therapy of murine leukemia with cyclophosphamide and immune Lyt2+ cells: cytolytic T cells can mediate eradication of disseminated leukemia . J. Immunol. , 136 , 1917 – 1922 ( 1986. ). [PubMed] [Google Scholar]
  • 26. ) Udono , H. , Mieno , M. , Shiku , H. and Nakayama , E.The roles of CD8+ and CD4+ cells in tumor rejection . Jpn. J. Cancer Res. , 80 , 649 – 654 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. ) Yoshimura , A. , Shiku , H. and Nakayama , E.Rejection of an I‐A+ variant line of FBL‐3 leukemia by cytotoxic T lymphocytes with CD4+ and CD4− CD8− T cell receptor‐αβ phenotypes generated in CD8‐depleted C57BL/6 mice . J. Immunol. , 150 , 4900 – 4910 ( 1993. ). [PubMed] [Google Scholar]
  • 28. ) Zinkernagel , R. M.H‐2 restriction of virus‐specific T‐cell‐mediated effector functions in vivo. II Adoptive transfer of delayed‐type hypersensitivity to murine lymphocytic choriomeningitis virus is restricted by the K and D region of H‐2 . J. Exp. Med. , 144 , 776 – 787 ( 1976. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. ) Hamaoka , T. and Fujiwara , H.Phenotypically and functionally distinct T‐cell subsets in anti‐tumor responses . Immunol. Today , 8 , 267 – 269 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 30. ) Askenase , P. W. , Bursztajn , S. , Gershon , M. D. and Gershon , R. K.T cell‐dependent mast cell degranulation and release of serotonin in murine delayed‐type hypersensitivity . J. Exp. Med. , 152 , 1358 – 1374 ( 1980. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. ) Askenase , P. W. , Metzler , C. M. and Gershon , R. K.Localization of leucocytes in site of delayed‐type hypersensitivity and in lymph nodes: dependence on vasoactive amines . Immunology , 47 , 239 – 246 ( 1982. ). [PMC free article] [PubMed] [Google Scholar]
  • 32. ) Maeda , Y. , Watanabe , T. , Chihara , G. and Rokutanda , M.T‐cell mediated vascular dilatation and hemorrhage induced by antitumor polysaccharides . Int. J. Immunopharm. , 6 , 493 – 501 ( 1984. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Maeda , Y. , Sakaizumi , M. , Moriwaki , K. and Yonekawa , H.Genetic control of the expression of two biological activities of an antitumor polysaccharide, Lentinan . Int. J. Immunopharm. , 13 , 977 – 986 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Homma , R. and Kuratsuka , K.The histamine‐sensitizing activity of lentinan, an antitumor polysaccharide . Experientia , 29 , 290 – 293 ( 1973. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES