Skip to main content
PMC home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1989 Nov;80(11):1089–1097. doi: 10.1111/j.1349-7006.1989.tb02264.x

Synergy of Nocardia rubra Cell Wall Skeleton and Interleukin 2 in the in vivo Induction of Murine Lymphokine‐activated Killer Cell Activity

Ichiro Kawase 1,✉, Kiyoshi Komuta 1, Takuma Shirasaka 1, Hideki Hara 1, Yoshiro Tanio 1, Masatoshi Watanabe 1, Shin'ichi Saito 1, Toshiyuki Ikeda 1, Tomiya Masuno 1, Susumu Kishimoto 1, Yuichi Yamamura 1
PMCID: PMC5917915  PMID: 2514171

Abstract

Combination of an ip injection of Nocardia rubra cell wall skeleton (N‐CWS) and 3 daily sc injections of human recombinant interleukin 2 (rIL 2) into C3H/HeN mice resulted not only in a significant increase in the number of peritoneal cells (PC) but also in a potent induction of their lymphokine‐activated killer (LAK) activity, compared with results obtained with N‐CWS or rIL 2 alone. The augmented LAK activity of PC was mediated by nonadherent, nonphagocytic, Thy‐1.2+∼− and asialo GM1+ cells. Nonadherent PC induced by an ip injection of N‐CWS bound more 125I‐labeled rIL 2 than did normal, nonadherent PC, and generated high LAK activity when cultured overnight with rIL 2. In contrast, normal, nonadherent PC responded only weakly to the overnight stimulation with rIL 2. The phenotype of N‐CWS‐induced PC with an elevated IL 2 responsiveness was Thy‐1.2+∼−, Lyt‐1.1−, Lyt‐2.1− and asialo GM1+, suggesting that the N‐CWS‐stimnlated LAK precursors were derived mainly from the NK cell lineage. However, mature T cells may also be involved in this mechanism, because N‐CWS failed to augment the IL 2 responsiveness of nonadherent PC in BALB/c nu/nu mice. Treatment of CS7BL/6N mice bearing solid Lewis lung carcinoma (3LL) tumors with an intratumoral injection of N‐CWS followed by 6 daily sc injections of rIL 2 resulted in the apparent suppression of tumor growth, while N‐CWS or rIL 2 alone produced no such suppression. These results suggest that N‐CWS augments the antitumor effect of rIL 2 by accumulating LAK precursors and elevating their responsiveness to rIL 2 at the injection site.

Keywords: N‐CWS, Human rIL 2, LAK cells

Full Text

The Full Text of this article is available as a PDF (531.5 KB).

REFERENCES

  • 1. ) Lafreniere , R. and Rosenberg , S. A.Successful im‐munotherapy of murine experimental hepatic metastases with lyraphokine‐activated killer cells and recombinant interleukin 2 . Cancer Res. , 45 , 3735 – 3741 ( 1985. ). [PubMed] [Google Scholar]
  • 2. ) Rosenberg , S. A. , Lotze , M. T. , Muul , L. M. , Chang , A. E. , Avis , F. P. , Leitman , S. , Linehan , W. M. , Robertson , C. N. , Lee , R. E. , Rubin , J. T. , Seipp , C. A. , Simpson , C. G. and White , D. E.A progress report on the treatment of 157 patients with advanced cancer using lymphokine‐activated killer cells and interleukin 2 or high‐dose interleukin 2 alone . N. Engl. J. Med. , 316 , 889 – 897 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Azuma , I. , Taniyama , T. , Yamawaki , M. , Sugimura , K. and Yamamura , Y.Adjuvant and antitumor activities of Nocardia rubra cell‐wall skeletons . Gann , 67 , 733 – 736 ( 1976. ). [PubMed] [Google Scholar]
  • 4. ) Yamamura , Y. , Ogura , T. , Sakatani , M. , Hirao , F. , Kishimoto , S. , Fukuoka , M. , Kawahara , M. , Furuse , K. , Kuwahara , O. , Ikegami , H. and Ogawa , N.Randomized controlled study of adjuvant immunotherapy with Nocardia rubra cell wall skeleton for inoperable lung cancer . Cancer Res. , 43 , 5575 – 5579 ( 1983. ). [PubMed] [Google Scholar]
  • 5. ) Hayashi , S. , Masuno , T. , Hosoe , S. , Kawase , I. , Sakatani , M. , Ogura , T. , Kishimoto , T. , Kishimoto , S. and Yamamura , Y.Augmented production of colony‐stimulating factor in C3H/HeN mice immunized with Nocardia rubra cell wall skeleton . Infect. Immun. , 52 , 128 – 133 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Masuno , T. , Hayashi , S. , Ito , M. , Ikeda , T. , Ogura , T. , Kishimoto , S. and Yamamura , Y.Mechanism(s) of in vitro macrophage activation with Nocardia rubra cell wall skeleton: the effect on macrophage activating factor production by lymphocytes . Cancer Immunol. Immunother. , 22 , 132 – 138 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. ) Izumi , S. , Ueda , H. , Okuhara , M. , Aoki , H. and Yamamura , Y.Effect of Nocardia rubra cell wall skeleton on murine interferon production in vitro . Cancer Res. , 46 , 1960 – 1965 ( 1986. ). [PubMed] [Google Scholar]
  • 8. ) Izumi , S. , Hirai , O. , Hayashi , K. , Konishi , Y. , Okuhara , M. , Kohsaka , M. , Aoki , H. and Yamamura , Y.Induction of a tumor necrosis factor‐like activity by Nocardia rubra cell wall skeleton . Cancer Res. , 47 , 1785 – 1792 ( 1987. ). [PubMed] [Google Scholar]
  • 9. ) Kato , K. , Yamada , T. , Kawahara , H. , Onda , T. , Asano , T. , Sugino , H. and Kakinuma , A.Purification and characterization of recombinant human interleukin 2 produced in Escherichia coli . Biochem. Biophys. Res. Commun. , 130 , 692 – 699 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Hinuma , S. , Naruo , K. , Shiho , O. and Tsukamoto , K.Characteristics of murine non‐specific killer cells induced in vivo by recombinant human interleukin 2 . Immunology , 59 , 251 – 259 ( 1986. ). [PMC free article] [PubMed] [Google Scholar]
  • 11. ) Kawase , I. , Komuta , K. , Hara , H. , Inoue , T. , Hosoe , S. , Ikeda , T. , Shirasaka , T. , Yokota , S. , Tanio , Y. , Masuno , T. and Kishimoto , S.Combined therapy of mice bearing a lymphokine‐activated killer‐resistant tumor with recombinant interleukin 2 and an antitumor monoclonal antibody capable of inducing antibody‐dependent cellular cytotox‐icity . Cancer Res. , 48 , 1173 – 1179 ( 1988. ). [PubMed] [Google Scholar]
  • 12. ) Robb , R. J. , Greene , W. C. and Rusk , C. M.Low and high affinity cellular receptors for interleukin 2: implications for the level of Tac antigen . J. Exp. Med. , 160 , 1126 – 1146 ( 1984. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. ) West , W. H. , Tauer , K. W. , Yannelli , J. R. , Marshall , G. D. , Orr , D. W. , Thurman , G. B. and Oldham , R. K.Constant‐infusion recombinant interleukin 2 in adoptive immunotherapy of advanced cancer . N. Engl. J. Med. , 316 , 898 – 905 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Hinuma , S. , Naruo , K. , Ootsu , K. , Hougan , T. , Shiho , O. and Tsukamoto , K.Suppression of tumor metastasis in mice by recombinant human interleukin 2: role of asialo GM1 positive cells . Immunology , 60 , 173 – 179 ( 1987. ). [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Morikawa , K. , Okada , F. , Hosokawa , M. and Kobayashi , H.Enhancement of therapeutic effect of recombinant interleukin 2 on a transplantable rat fibrosarcoma by the use of a sustained release vehicle, pluronic gel . Cancer Res. , 47 , 37 – 41 ( 1987. ). [PubMed] [Google Scholar]
  • 16. ) Grimm , E. A. , Ramsey , K. M. , Mazumder , A. , Wilson , D. J. , Djeu , J. Y. and Rosenberg , S. A.Lymphokine‐activated killer phenomenon: II. Precursor phenotype is serologically distinct from peripheral T lymphocytes, memory cytotoxic thymus‐derived lymphocytes, and natural killer cells . J. Exp. Med. , 157 , 884 – 897 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. ) Ogura , T. , Namba , M. , Hirao , F. , Yamamura , Y. and Azuma , I.Association of macrophage activation with antitumor effect on rat syngeneic fibrosarcoma by Nocardia rubra cell wall skeleton . Cancer Res. , 39 , 4706 – 4712 ( 1979. ). [PubMed] [Google Scholar]
  • 18. ) McIntosh , J. K. , Múle , J. J. , Merino , M. J. and Rosenberg , S. A.Synergistic antitumor effect of immunotherapy with recombinant interleukin 2 and tumor necrosis factor‐α . Cancer Res. , 48 , 4011 – 4017 ( 1988. ). [PubMed] [Google Scholar]
  • 19. ) Owen‐Schaub , L. B. , Gutterman , J. U. and Grimm , E. A.Synergy of tumor necrosis factor and interleukin 2 in the activation of human cytotoxic lymphocytes: effect of tumor necrosis factor‐α and interleukin 2 on the generation of human lymphokine‐activated killer cell cytotoxicity . Cancer Res. , 48 , 788 – 792 ( 1988. ). [PubMed] [Google Scholar]
  • 20. ) Chouaib , S. , Bertoglio , J. , Blay , J‐Y. , Marchiol‐Fournigault , C. and Fradelizi , D.Generation of lymphokine‐activated killer cells: synergy between tumor necrosis factor and interleukin 2 . Proc. Natl. Acad. Sci. USA , 85 , 6875 – 6879 ( 1988. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. ) Iigo , M. , Sakurai , M. , Tamura , T. , Saijo , N , and Hoshi , A.In vivo antitumor activity of multiple injections of recombinant interleukin 2, alone or in combination with three different types of recombinant interferon, on various syngeneic murine tumors . Cancer Res. , 48 , 260 – 264 ( 1988. ). [PubMed] [Google Scholar]
  • 22. ) Rosenberg , S. A. , Schwarz , S. L. and Spiess , P. J.Combination immunotherapy for cancer. Synergistic antitumor interactions of interleukin 2, alfa interferon, and tumor‐infiltrating lymphocytes . J. Natl Cancer Inst. , 80 , 1393 – 1397 ( 1988. ). [DOI] [PubMed] [Google Scholar]

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

RESOURCES