Abstract
The antigen complex A60 ofMycobacterium bovis bacillus Calmette-Guérin protected mice against experimental tuberculous infection, and prevented cancer development after challenge with EMT 6 cells. Although humoral and cellular immune reactions elicited by A60 in vivo remained unaffected in cases of tumor rejection, they were suppressed in the case of neoplastic growth. In the present work, these in vivo observations were analyzed by in vitro techniques. Activated macrophages played a major role, and cytolytic T lymphocytes a minor role, in A60-promoted cancer cell cytolysis leading to tumor rejection. In vitro, EMT 6 cells weakly inhibited the proliferation of A60-specific B lymphocytes and strongly inhibited the functions of activated macrophages. However, the collapse of both humoral and cellular immune reactions during the course of cancer development was also accompanied by an inhibitory action of EMT 6 cells on the multiplication and functions of A60-specific T lymphocytes. Tumor-dependent repression of macrophage activation was therefore due to both a direct action of tumor cells on macrophages and an indirect one via inhibition of macrophage-activating T cell functions. On the other hand, tumor-induced collapse of the anti-A60 Ig synthesis was mainly due to inhibition of B-cell-activating T cells, with a weaker direct effect of tumor cells on B lymphocytes. Consequently, A60 and tumor cells exert opposite effects on the immune system at several levels.
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Abbreviations
- EMT 6 :
-
mammary KHJJ carcinoma
- A60 :
-
the thermostable macromolecular antigen complex fromM. bovis
- PBS :
-
phosphate-buffered saline
- FCS :
-
fetal calf serum
- CTL :
-
cytotoxic T lymphocytes
- TIL :
-
tumor-infiltrating lymphocytes
References
Adams DO, Hamilton TA (1992) Molecular basis of macrophage activation: diversity and its origins. In: Lewis CE, McGee JO (eds) The Natural immune system. The macrophage IRL Oxford, pp 76–114
Askenase PW (1992) Delayed-type hypersensitivity recruitment of T cell subsets via antigen-specific non-IgE factors or IgE antibodies: relevance to asthma, autoimmunity and immune responses to tumors and parasites. Chem Immunol 54:166–211
Baldwin RW, Pimm MV (1978) BCG in tumor immunotherapy. Adv Cancer Res 28:91–147
Barth RJ, Bock SN, Mule JJ, Rosenberg SA (1990) Unique murine tumor-associated antigens identified by tumor infiltrating lymphocytes. J Immunol 144:1531–1537
Bartholomew B (1984) A rapid method for the assay of nitrate in urine using the nitrate reductase enzyme ofEscherichia coli. Food Chem Toxicol 22:541–543
Belledegrun A, Muul LM, Rosenberg SA (1988) Interleukin 2 expanded tumor-infiltrating lymphocytes in human renal cell cancer: isolation, characterization, and antitumor activity. Cancer Res 48:206–214
Benoit CA, Beschin A, Desmecht M, Deckeyser P, Cocito C (1989) Delayed hypersensitivity reactions by the mycobacterial antigen A60 and cutaneous testing in tuberculosis. Med Microbiol Immunol 178:105–112
Beschin A, Brijs L, De Baetselier P, Cocito C (1991) Mycobacterial proliferation in macrophages is prevented by incubation with lymphocytes activatedin vitro with a mycobacterial antigen complex. Eur J Immunol 21:793–797
Brooks WH, Netsky MG, Normansell DE, Horwitz DA (1972) Depressed cell-mediated immunity in patients with primary intracranial tumors. Characterization of a humoral immunosuppressive factor J Exp Med 136:1631–1647
Cerny J, Stiller RA (1975) Immunosuppresion by spleen cells from Moloney leukemia. Comparison of the suppressive effect on antibody response and on mitogen-induced response. J Immunol 115:943–947
Closs O, Harboe M, Axelsen NH, Burch-Christensen K, Magnusson M (1980) The antigens ofMycobacterium bovis, strain BCG, studied by crossed immunoelectrophoresis: a reference system. Scand J Immunol 12:249–263
Cocito C, Vanlinden F (1986) Preparation and properties of antigen 60 fromMycobacterium bovis BCG. Clin Exp Immunol 66:262–272
Cocito C, Vanlinden F (1995) Composition and immunoreactivity of the A60 complex and other cell fractions fromMycobacterium bovis BCG. Scand J Immunol 41:179–187
Cocito C, Baelden M-C, Benoit C (1987) Immunological properties of antigen 60 of BCG. Induction of humoral and cellular immunity reactions. Scand J Immunol 25:579–585
Coetsier C, Baelden M-C, Coene M, Cocito C (1994) Immunological analysis of the components of the antigen complex A60 ofMycobacterium bovis BCG. Clin Diag Lab Immunol 1:139–144
Ding AH, Nathan CF, Stuehr DJ (1988) Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. J Immunol 141:2407–2412
Fabre I, L'Homme L, Bruneteau M, Michel G, Cocito C (1986) Chemical composition of antigen A60 fromMycobacterium bovis BCG, Scand J Immunol 24:591–602
Fong TAT, Mosmann TR (1989) The role of IFN-γ in delayed-type hypersensitivity mediated by Th1 clones. J Immunol 143:2887–2893
Gilot P, Coene M (1994) Thermostable macromolecular antigens from mycobacteria. Can J Microbiol: 40:605–611
Green LC, Wagner DA, Glogowski, Skipper PL, Wishnok JS, Tannenbaum SR (1982) Analysis of nitrate, nitrite and [15N] nitrate in biological fluids. Anal Biochem 126:31–138
Hersh EM Gutterman JU, Mavligit GM (1977) BCG as adjuvant immunotherapy for neoplasia. Annu Rev Med 28:489–515
Hubbard RD, Flory CM, Collins FM, Cocito C (1992) Immunization of mice with antigen A60 ofMycobacterium bovis BCG. Clin Exp Immunol 88:129–131
Ishii Y, Matsuura A, Takami T, Uede T, Ibayashi Y, Uede T, Imamura M, Kikuchi K, Kikuchi Y (1984) Lymphoid cell subpopulations infiltrating into autologous rat tumors undergoing rejection. Cancer Res 44:4053–4058
Kawase I, Komuta K, Namba M, Yokota S, Ogura T, Kishomoto S (1986) Macrophage tumoricidal activity as a possible antitumor mechanism associated with the local injection of allogeneic spleen cells in rats. Cancer Res 46:1047–1054
Kedar E, Klein E (1992) Cancer immunotherapy: are the results discouraging? Adv Cancer Res 59:245
Kersey JH, Spector BD, Good RA (1973) Immunodeficiency and cancer. Adv Cancer Res 18:211–219
Kung JF, Brooks SB, Jakway JP, Leonard LL, Talmage DW, Suppression ofin vitro cytotoxic response by macrophages due to induced arginase. J Exp Med 146:665–672
Maes H, Cocito C (1996) Synthesis of cytokines during tumor development in mice immunized with the mycobacterial antigen complex A60. Scand J Immunol (in press)
Maes H, Taper H, Cocito C (1995) Alteration of the immune response during cancer development and prevention by administration of a mycobacterial antigen. Scand J Immunol 41:53–64
Miescher S, Whiteside TL, De Tribolet N, Von Fliedner V (1988) In situ characterization, clonogenic potential, and antitumor cytolytic activity of T lymphocytes infiltrating human brain cancers. J Neurosurg 68:438–448
Milas L, Scott MT (1978) Antitumor activity ofCorynebacterium parvum. Adv Cancer Res 26:257–306
Remels L, Fransen L, Huygen K, De Baetselier P (1990) Poly I: C activited macrophages are tumoricidal for TNF-α-resistant 3LL tumor cells. J Immunol 144:4477–4486
Rockwell SC, Kallman RF, Fajardo LP (1972) Characteristics of a serially transplanted mouse mammary tumor and its tissueculture-adapted derivative. J Natl Cancer Inst 49:735–749
Rook GAW, Steele J, Uman S Dockrell M (1985) A simple method for the solubilisation of reduced NBT, and its use as a colorimetric assay for activation of human macrophages by γ-interferon. J Immunol Methods 82:161–167
Rubbert A, Manger B, Lang N, Kalden GR, Platzer E (1991) Functional characterization of tumor-infiltrating lymphocytes, lymph-node lymphocytes and peripheral-blood lymphocytes from patients with breast cancer. Int J Cancer 49:25–31
Sawamura Y, Hosokawa M, Kupper MC, Kobayashi H, Aida T, Abe H, De Tribolet N (1989) Antitumor activity and surface phenotypes of human glioma-infiltrating lymphocytes afterin vitro expansion in the presence of interleukin 2. Cancer Res 49:1843–1849
Siegel BV (1978) Tumor immunity. Am J Pathol 93:515–518
Spiess PJ, Yang JC, Rosenberg SA (1987) In vitro antitumor activity of tumor-infiltrating lymphocytes expanded in recombinant interleukin-2. J Natl Cancer Inst 79:1067–1075
Stutman O (1975) Immunodepression and malignancy. Adv Cancer Res 22:261–422
Svennevig JL, Svaar H (1979) Content and distribution of macrophages and lymphocytes in solid malignant human tumor. Int J Cancer 24:754–758
Urban JL, Schreiber H (1992) Tumor antigens. Annu Rev Immunol 10:617–632
Vaage J, Pepin KG (1985) Morphological observation during developing concomitant immunity against a C3H/He mammary tumor. Cancer Res 45:659–666
Vessiere F, Georelette M, Warnier G, Leclerc JC, Van Pel A, Boon T (1982) Immunogenic variants obtained by mutagenesis of mouse Lewis Lung Carcinoma. Recognition of variant-specific antigens by cytolytic T lymphocytes. Eur J Cancer Clin Oncol 18:867–874
Wilson KM, Lord EM (1987) Specific (EMT6) and non-specific (WEHI-164) cytolytic activity by host cells infiltrating tumor spheroids Br J Cancer 55:141–146
Young MR, Wheeler E, Newby MJ (1986) Macrophage-mediated suppression of natural killer cell activity in mice bearing Lewis lung carcinoma. J Natl Cancer Inst 76:745–750
Young MR, Wright MA, Coogan M, Young ME, Bagash J (1992) Tumor-derived cytokines induce bone marrow suppressor cells that mediated immunosuppression through transforming growth factor b. Cancer Immunol Immunother 35:14–18
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This study was supported by a grant from ANDA Biologicals, Strasbourg, France
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Maes, H., Cocito, C. In vitro analysis of cancer prevention by a mycobacterial antigen complex and of cancer-promoted inhibition of immune reactions. J Cancer Res Clin Oncol 122, 727–734 (1996). https://doi.org/10.1007/BF01209120
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DOI: https://doi.org/10.1007/BF01209120