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Augmentation of antitumor immunity in regional lymph nodes by local immunotherapy

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Biotherapy

Abstract

We have previously reported that the antitumor effect of OK-432, a streptococcal preparation, is markedly augmented when injected intratumorally together with fibrinogen (OK-432/fbg) [1]. In order to elucidate the effects of this immunotherapy on regional lymph nodes (RLN), we carried out both morphological and functional analyses of the RLN from colonic cancer patients treated with OK-432/ fbg. Computer-aided morphometry revealed that the maximal cross-sectional areas and the broadest diameters of the RLN were significantly greater (p<0.01) in patients who had undergone local immunotherapy than in patients who had not. The component structures of RLN, such as sinus, follicle and paracortex, were all enlarged in the OK-432/fbg-treated patients, and necrosis of metastatic tumors was observed. RLN lymphocytes recovered from OK-432/fbg treated patients showed elevated reactivity to phytohemagglutinin (PHA) and the stimulation index was clearly higher than that of control patients. Flow cytometric analysis revealed a predominance of T-cells, especially CD4 subsets, and higher positivity for both CD25 and HLA-DR. Furthermore, RLN lymphocytes killed more effectively K562 and Daudi cells in the patients who had had immunotherapy. These results suggest that the effect of local immunotherapy with OK-432/fbg is not restricted to the site of injection but extends to the lymph nodes, and contributes to tumor regression through the augmentation of cellular immunity.

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Abbreviations

RLN:

regional lymph node(s)

OK-432/fbg:

OK-432/fibrinogen solution

PHA:

phytohemagglutinin

NK:

natural killer

LAK:

lymphocyte activated killer

References

  1. 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.

    PubMed  Google Scholar 

  2. Fisher B, Fisher ER. Studies concerning the regional lymph node in cancer. I. Initiation of immunity. Cancer 1971; 27: 1001–4.

    PubMed  Google Scholar 

  3. Fisher B, Fisher ER. Studies concerning the regional lymph node in cancer. II. Maintenance of immunity. Cancer 1972; 29: 1496–501.

    PubMed  Google Scholar 

  4. Fisher B, Saffer E, Fisher ER. Studies concerning the regional lymph node in cancer. IV. Tumor inhibition by regional lymph node cells. Cancer 1974 33: 631–6.

    PubMed  Google Scholar 

  5. Kawase I, Uemiya M, Yoshimoto T, Ogura T, Hirano F, Yamamura Y. Effect of Nocardia rubra cell wall skeleton on T-cell mediated cytotoxicity in mice bearing syngeneic sarcoma Cancer Res 1981; 41: 660–6.

    PubMed  Google Scholar 

  6. Yaita H, Yasumoto K, Nagashima A, Sugimachi K, Nomoto K. Anti-tumor activity of regional lymph node lymphocytes in patients with lung cancer. J Surg Oncol 1988; 38: 165–72.

    PubMed  Google Scholar 

  7. Watanabe Y, Hasizume Y, Shimizu J, Yoshida M, Watanabe S, Iwa T, Sakai S, Migita S, Sato H, Murayama T, Koshimura S, Saito M. Functional character and augmentation of lymphocytes in regional lymph nodes of patients with lung cancer. Am Rev Respir Dis. 1990; 142: 769–74.

    PubMed  Google Scholar 

  8. Micel RA, Kessler DJ, Taylor JMG, Lichtenstein A. Natural killer cell cytotoxicity in the peripheral blood, cervical lymph nodes, and tumor of head and neck cancer patients. Cancer Res. 1988; 48: 5017–22.

    PubMed  Google Scholar 

  9. Niitsuma M, Golub SH, Edelstein R, Holmes EC. Lymphoid cells infiltrating human pulmonary tumors; effect of intralesional BCG injection. J Nat. Cancer Inst. 1981; 67: 997–1003.

    PubMed  Google Scholar 

  10. Onishi T, Machida F, Masuda T, Hatano H, Shirakawa T, Natori M, Hamamoto M, Matsuoka Y. Assessment of tumour-infiltrating lymphocytes, regional lymph node lymphocytes and peripheral blood lymphocytes and their reaction to interferon-gamma in patients with renal carcinoma Br. J Urol. 1991; 67: 459–66.

    Google Scholar 

  11. 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 human interferon gamma. J Clin Lab Immunol. 1988; 27: 115–20.

    PubMed  Google Scholar 

  12. 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.

    Google Scholar 

  13. Torisu M, Katano M, Kimura Y, Itou 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  Google Scholar 

  14. 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 93; 1983: 365–73.

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  16. Uchida A, Michise M, Hoshino T. Intrapleural 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.

    PubMed  Google Scholar 

  17. 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  Google Scholar 

  18. Vinzenz K, Porteder H, Matejka M, Neuhold N, Watzek G, Mickishe M. Modulation of NK activity in regional lymph nodes by preoperative immunotherapy with OK-432 in patients with cancer of the oral cavity. Cancer Detection Prevention Suppl 1987; 1: 463–75.

    Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  21. 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 Immunol 1987; 139: 3281–6.

    PubMed  Google Scholar 

  22. 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  Google Scholar 

  23. Uchiyama T, Broder 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  Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  26. Black MM, Freeman C, Mork T, Harvei S, Cutler SJ. Prognostic significance of microscopic structure of gastric carcinomas and their regional lymph nodes. Cancer 1971; 27:703–11.

    PubMed  Google Scholar 

  27. Black MM, Opler SR, Speer FD. Microscopic structure of gastric carcinomas and their regional lymph nodes in relation to survival. Surg Gyneco Obstet 1954; 98: 725–34.

    Google Scholar 

  28. Friedell GH, Millis RR, Sato T, Suchi T, Shikata I, Chaudary MA, Hayward JL. Breast cancer in English and Japanese women: Prognostic significance of sinus histiocytosis and germinal center hyperplasia in axillary lymph nodes. Breast Cancer Res. Treat. 1991; 18: 573–6.

    Google Scholar 

  29. Murray D, Hreno A, Dutton J, Hampson LG. Prognosis in colon cancer. A pathologic reassessment. Arch. Surg. 1975; 110: 908–13.

    PubMed  Google Scholar 

  30. Patt DJ, Brymes RK, Vardiman JW, Coppleson LW. Mesocolic lymph node histology as an important prognostic indicator for patients with carcinoma of the sigmoid colon: An immunomorphologic study. Cancer 1975; 35: 1388–97.

    PubMed  Google Scholar 

  31. 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. 192; 83: 20–3.

  32. 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.

    PubMed  Google Scholar 

  33. Lydyard P, Grossi C. Cells involved in the immune response. In: Roitt I, Brostoff J, Male D. eds. Immunology. London: Grower Medical Publishing, 1989: 2.1–2.18.

    Google Scholar 

  34. Fisher B, Saffer E, Fisher E. Studies concerning the regional lymph node in cancer. III. Response of regional lymph node cells from breast and colon cancer patients to PHA stimulation. Cancer 1972; 30: 1202–15.

    PubMed  Google Scholar 

  35. Smith KA. Interleukin-2: inception, impact and implications. Science 1988; 240: 225–41.

    Google Scholar 

  36. Takeuchi Y, Yosie H, Hara K. Expression of interleukin-2 receptor and HLA-DR on lymphocyte subsets of gingival crevicular fluid in patients with periodontitis. J Periodont Res 1991: 26; 502–10.

    PubMed  Google Scholar 

  37. Sato T, Fujii M, Satoh H, Itoh T, Rikiishi H, Kumagai K. Polyclonal activation of human lymphocytes and induction of cytotoxic lymphocytes by streptococcal preparations. Biotherapy 1992; 4: 53–63.

    PubMed  Google Scholar 

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Sakita, I., Monden, T., Nagaoka, H. et al. Augmentation of antitumor immunity in regional lymph nodes by local immunotherapy. Biotherapy 6, 103–112 (1993). https://doi.org/10.1007/BF01877423

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