Skip to main content
SpringerLink
Log in

Augumentation of splenic antitumor immunity by local immunotherapy in gastric cancer patients

  • Published:
Biotherapy

Abstract

We previously reported that the antitumor effect of OK-432, a streptococcal preparation, was markedly augmented when this agent was injected into tumors together with fibrinogen. In order to elucidate the effect of this treatment on the spleen, we assessed splenic function in gastric cancer patients receiving preoperative local immunotherapy with OK-432 and fibrinogen. Immunohistochemical studies of the spleen at 7 days after intratumoral injection therapy revealed numerous macrophages phagocytizing OK-432 in the splenic sinuses. Phenotypic analysis of splenocytes by flow cytometry revealed an increase in the CD4/CD8 ratio and in the expression of HLA-DR, CD25, and Leu M3 by splenic T cells of the patients treated with OK-432 plus fibrinogen when compared to patients treated with OK-432 alone or untreated patients. Splenic T cells from patients treated with OK-432 plus fibrinogen showed significantly higher cytotoxicity against Daudi and K562 cells than T cells from control patients (p<0.05), and culture of these splenic T cells with recombinant IL-2 induced the expansion of lymphokine-activated killer cells. These results demonstrate that local immunotherapy with a mixture of OK-432 and fibrinogen effectively augumented splenic antitumor immunity in gastric cancer patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

OK-432/fbg:

a mixture of OK-432 and fibrinogen

LAK:

lymphokine-activated killer

References

  1. Sekimoto M, Kokunai I, Shimano T, Kobayashi T, Takeda T, Haruna N, Yamamoto A, Mori T. Production of tumor necrosis factor(TNF) by monocytes from cancer patients and healthy subjects induced by OK-432 in vitro, and its augmentation by human interferon gamma. J Clin Lab Immunol. 1988; 27: 115–20.

    PubMed  CAS  Google Scholar 

  2. Haruna N, Monden T, Morimoto H, Murotani M, Yagyu T, Nagaoka H, Shimano T, Mori T. Use of a rapid microwave fixation technique for immunocytochemical demonstration of tumor necrosis factor, interleukin-1a, and interleukin-1b in activated human peripheral mononuclear cells. Acta Histochem Cytochem. 1990; 23: 563–72.

    CAS  Google Scholar 

  3. Torisu M, Katano M, Kimura Y, Itoh H, Takesue M. New approach to management of malignant ascites with a Streptococcal preparation, OK-432. I. Improvement of host immunity and prolongation of survival. Surgery 1983; 93: 357–64.

    PubMed  CAS  Google Scholar 

  4. Katano M, Torisu M. New approach to management of malignant ascites with a Streptococcal preparation, OK-432. II. Intraperitoneal inflammatory cell-mediated tumor cell destruction, Surgery 1983; 93: 365–73.

    PubMed  CAS  Google Scholar 

  5. Watanabe Y, Iwa T. Clinical value of immunotherapy for lung cancer by the Streptococcal preparation OK-432. Cancer 1984; 53: 248–53.

    Article  PubMed  CAS  Google Scholar 

  6. Uchida A, Michise M, Hoshino T. Intraperitoneal administration of OK-432 in cancer patients: Augmentation of autologous tumor killing activity of tumor associated large granular lymphocytes. Cancer Immunol Immunother 1984; 18: 5–12.

    Article  PubMed  CAS  Google Scholar 

  7. Watanabe Y, Iwa T. Clinical value of immunotherapy with the Streptococcal preparation OK-432 in non-small cell lung cancer. J Biol Response Mod 1987; 6: 169–80.

    PubMed  CAS  Google Scholar 

  8. Monden T, Morimoto H, Shimano T, Yagyu T, Murotani M, Nagaoka H, Kawasaki Y, Kobayashi T, Mori T. Use of fibrinogen to enhance the antitumor effect of OK-432. A new approach to immunotherapy for colorectal carcinoma. Cancer 1992; 69: 636–42.

    Article  PubMed  CAS  Google Scholar 

  9. Sakita I, Monden T, Nagaoka H, Katsumoto Y, Wakasugi T, Tomita N, Takeda T, Kobayashi T, Shimano T, Mori T. Augmentation of antitumor immunity in regional lymph nodes by local immunotherapy. Biotherapy 1993; 6: 103–112.

    Article  PubMed  CAS  Google Scholar 

  10. Nagaoka H, Monden T, Sakita I, Katsumoto Y, Wakasugi T, Kawasaki Y, Takeda T, Yagyu T, Morimoto H, Kobayashi T, Shimano T, Mori T. Establishment of cytotoxic CD4+ T cell clones from cancer patients treated by local immunotherapy. Biotherapy 1992; 5: 241–50.

    Article  PubMed  CAS  Google Scholar 

  11. Yagyu T, Monden T, Tamaki Y, Morimoto H, Takeda T, Kobayashi T, Shimano T, Murakami H, Mori T. Use of a local immunotherapy as an adjunctive tool for the generation of human monoclonal antibodies from regional lymph nodes of colonic cancer patients. Jpn J Cancer Res. 1992; 83: 20–3.

    PubMed  CAS  Google Scholar 

  12. Takahashi M, Fujimoto S. Clinical studies on the correlation between immunologic status and total gastrectomy combined with splenectomy. Jpn J Surg. 1980; 10: 100–4.

    Article  PubMed  CAS  Google Scholar 

  13. Tetsuya Toge, Yoshihiro Seto, Katsumasa Kuroi, Hirofumi Yamada, Kiyoshi Aratani, Tsuyoshi Fujita, Etsuro Yanagawa, Takao Hattori. Relationship of the distribution of Leu-2+ cells with suppressor cell activities in the spleen and lymphocytes from gastric cancer. Jpn J Surg. 1987; 17: 72–7.

    Article  Google Scholar 

  14. Takahashi M, Fujimoto M, Takai M, Ohno K, Endoh F, Masuda Y, Masuda Y, Obata G. Two-color flow cytometric analysis of splenic lymphocyte subpopulations in patients with gastric cancer. Jpn J Surg. 1990; 22: 35–9.

    Google Scholar 

  15. Japanese Research Society for Gastric Cancer. The general rules for gastric cancer study in surgery and pathology. Jpn J Surg. 1981; 11: 127–45.

    Article  Google Scholar 

  16. Neckers LM, Cossman J. Transferrin receptor induction in mitogen-stimulated human T lymphocytes is required for DNA synthesis and cell devision and is regulated by interleukin 2. Proc Natl Acad Sci USA. 1983; 80: 3494–8.

    Article  PubMed  CAS  Google Scholar 

  17. Gransbacher B, Zier KS. Regulation of HLA-DR, DP, and DQ expression in activated T cells. Cell Immunol. 1988; 117: 22–34.

    Article  Google Scholar 

  18. Moriya N, Sanjoh K, Yokoyama S, Hayashi T. Mechanisms of HLA-DR antigen expression in phytohemagglutinin-activated T cells in man/Requirement of T cell recognition of self HLA-DR antigen expressed on the surface of monocytes. J Immuno. 1987; 139: 3281–6.

    CAS  Google Scholar 

  19. Stefanini GF, Bercovich E, Mazzeo V, Grigioni WF, Emili E, d’Errico A, Lo Cigno M, Tamagnini N, Mazzetti M. Class I and class II HLA antigen expression by transitional cell carcinoma of the bladder: correlation with T-cell infiltration and BCG treatment. J Urol. 1989; 141: 1449–53.

    PubMed  CAS  Google Scholar 

  20. Uchiyama T, Broader S, Waldmann TA. A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. I. Production of anti-Tac monoclonal antibody and distribution of Tac(+) cells. J Immunol. 1981; 126: 1393–7.

    PubMed  CAS  Google Scholar 

  21. Theyer G, Kramer G, Assmann I, Sherwood E, Preinfalk W, Marberger M, Zechner O, Steiner GE. Phenotypic characterization of infiltrating leucocytes in benign prostatic hyperplasia. Lab Invest. 1992; 66: 96–107.

    PubMed  CAS  Google Scholar 

  22. Buring J, Kardol M, Arentzen R. Carboxyfluorescein fluorochromasia assays. J Immunol Methods. 1980; 33: 33–44.

    Article  Google Scholar 

  23. Nordlund JJ, Gershon RK. Splenic regulation of the clinical appearance of small tumors. J Immunol. 1975; 114: 1486–90.

    PubMed  CAS  Google Scholar 

  24. Yamagishi H, Pellis NR, Kahan BD. Effect of splenectomy upon tumor growth: Characterization of splenic tumorenhancing cells in vivo. Surgery 1980; 87: 655–61.

    PubMed  CAS  Google Scholar 

  25. Yamagishi H, Pellis NR, Kahan BD. Streptococcal immunotherapy of a chemically induced murine fibrosarcoma: effect of dose, route, Sham surgery, and splenectomy on adjuvant action. Cancer Immunol Immunother. 1980; 9: 63–7.

    Article  Google Scholar 

  26. Falk S, Seipelt G, Muller H, Stutte HJ. Immunohistochemical assessment of splenic lymphocyte and macrophage subpopulations in patients with gastric cancer. Cancer. 1989; 64: 1646–51.

    Article  PubMed  CAS  Google Scholar 

  27. Yanagawa E, Toge T, Sawamura A, Kegoya Y, Baba N, Hattori T. The regulation of natural killer cell activity by splenic nonspecific suppressor cells and its modification in cancer patients. Jpn J Surg. 1988; 18: 660–7.

    Article  PubMed  CAS  Google Scholar 

  28. Toge T, Kameda A, Yamada H, Seto Y, Aratani K, Fujita T, Hattori T. Role of the spleen on immunosuppression in esophageal and gastric cancer. Jpn J Surg. 1986; 16: 330–5.

    Article  PubMed  CAS  Google Scholar 

  29. Akiyoshi T, Koba F, Arinaga S, Tsuji H. Activated killer cell activity of spleen cells from patients with gastric carcinoma. J Clin Lab Immunol. 1987; 23: 197–201.

    PubMed  CAS  Google Scholar 

  30. Watanabe S, Sendo F, Kimura S, Arai S. Activation of cytotoxic polymorphonuclear leukocyte by in vivo administration of a streptococcal preparation, OK-432. J Natl Cancer Inst. 1984; 72: 1365–70.

    Google Scholar 

  31. Saito M, Nanjo M, Aonuma E, Noda T, Nakadate I, Ebina T, Ishida N. Activated macrophages are responsible for the tumor-inhibitory effect in mice receiving intravenous injection of OK-432. Int J Cancer. 1984; 33: 271–6.

    Article  PubMed  CAS  Google Scholar 

  32. De Ley M, Claeys H. Streptococcal preparation OK-432-induced interferon in human leukocytes: Purification and characterization. Int Archs Allergy appl Immun. 1984; 74: 21–8.

    Google Scholar 

  33. Saji S, Umemoto T, Tachibana S, Takao H, Sakata K. Antitumor effects of neutrophils induced by local administration of a nonspecific immunopotentiator, OK-432: Clinical and experimental studies. In: Ishida N(ed) Mechanisms of antitumor effects of OK-432. Excerpta Medica, Tokyo. 1986: 34–42.

    Google Scholar 

  34. Yang KD, Stone RD, Lee CS, Chao TY, Cheng SN, Shaio MF. Effect of picibanil (OK-432) on neutrophil-mediated antitumor activity: implication of monocyte-derived neutrophilactivating factors. Cancer Immunol Immunothe. 1992; 27: 277–82.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Second Department of Surgery, Osaka University Medical School, 2-2, Yamada-Oka, Suita, 565, Osaka, Japan

    Taro Wakasugi M.D., Tsutomu Takeda, Takushi Monden, Yoshihiro Katsumoto, Isao Sakita, Hirohito Nagaoka, Mutsumi Fukunaga, Naohiro Tomita, Tetsuro Kobayashi, Hitoshi Shiozaki, Takashi Shimano & Morito Monden

Authors
  1. Taro Wakasugi M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tsutomu Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takushi Monden
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshihiro Katsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isao Sakita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hirohito Nagaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mutsumi Fukunaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naohiro Tomita
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tetsuro Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hitoshi Shiozaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takashi Shimano
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Morito Monden
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wakasugi, T., Takeda, T., Monden, T. et al. Augumentation of splenic antitumor immunity by local immunotherapy in gastric cancer patients. Biotherapy 10, 99–106 (1997). https://doi.org/10.1007/BF02678536

Download citation

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02678536

Key words

Search

Navigation