Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Induction of effective antitumor immune responses in a mouse bladder tumor model by using DNA of an α antigen from mycobacteria

Cancer Gene Therapy volume 8, pages 483–490 (2001)Cite this article

Abstract

One of the main objectives of cancer immunotherapy is the activation and increase in number of antitumor effector cells. Recently, genetically modified tumor cell vaccines have been proposed for elicitation of antitumor effector cells. Native α antigen (α Ag) (also known as MPT59 and antigen 85B) of mycobacteria, which cross-reacts among mycobacteria species, may play an important biological role in host–pathogen interaction because it elicits various helper T-cell type 1 immune responses. To assess the induction of antitumor immune responses by α Ag, mouse tumor cell lines transfected with cDNA of α Ag from Mycobacterium kansasii were established, and the possibility of producing a tumor cell vaccine for induction of antitumor effects was explored. Transfection of tumor cell lines with an α Ag gene lead to primary tumor rejection and the establishment of protective immunity to nontransfected original tumor cell lines in Mycobacterium bovis bacillus Calmette-Gurin (BCG)-primed and unprimed mice. Mice immunized with tumor cell lines transfected with the α Ag gene showed delayed-type hypersensitivity responses in vivo and proliferative responses together with induction of interferon-γ of spleen cells against nontransfected wild-type tumor cell lines in in vitro experiments. Moreover, immunization of mice with α Ag–expressing tumor cells elicited tumor-specific and cytotoxic T lymphocyte (CTL) epitope peptide-specific CD8 + CTLs. The results of this study provided evidence of the potential usefulness of α Ag in tumor cell vaccines. Cancer Gene Therapy (2001) 8, 483–490

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Townsend A, Bdmer H . Antigen recognition by class I-restricted T lymphocytes Annu Rev Immunol 1989 7: 601–624

    Article  CAS  PubMed  Google Scholar 

  2. Germain RN, Margulies D . The biochemistry and cell biology of antigen processing and presentation Annu Rev Immunol 1993 11: 403–450

    Article  CAS  PubMed  Google Scholar 

  3. Kourisky P, Jaulin C, Levy V . The structure and function of MHC molecules. Possible implications for the control of tumor growth by MHC restricted T cells Semin Cancer Biol 1991 2: 275–282

    Google Scholar 

  4. Sheu BC, Hsu SM, Ho HN, et al . Tumor immunology — when a cancer cell meets the immune cells J Formosan Med Assoc 1999 98: 730–735

    CAS  PubMed  Google Scholar 

  5. Marincola FM, Jafee EM, Hicklin DJ, et al . Escape of human solid tumors from T cell recognition: molecular mechanisms and functional significance Adv Immunol 2000 74: 181–273

    Article  CAS  PubMed  Google Scholar 

  6. Lotte A, Wasz-Hocket O, Poisson N, et al . BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics Adv Tuberc Res 1984 21: 107–193

    CAS  PubMed  Google Scholar 

  7. Luelmo F . BCG vaccination Am Rev Respir Dis 1982 125: 70–72

    CAS  PubMed  Google Scholar 

  8. Lamm DL . Long-term results of intravesical therapy for superficial bladder cancer Urol Clin North Am 1992 19: 573–580

    Article  CAS  PubMed  Google Scholar 

  9. Mastrangelo MJ, Baker AR, Katz HR . Cutaneous melanomain cancer in cancer In: Devita VT Jr, ed. Principles and Practice in Oncology, 2nd ed Philadelphia: J.B. Lippincott 1985 1371–1442

  10. Morales A, Nickel JC . Immunotherapy for superficial bladder cancer. A developmental and clinical overview Urol Clin North Am 1992 19: 549–556

    Article  CAS  PubMed  Google Scholar 

  11. Morton DL, Foshag LJ, Hoon DS, et al . Prolongation of survival in metastatic melanoma after active specific immunotherapy with a new polyvalent melanoma vaccine Ann Surg 1989 216: 463–482

    Article  Google Scholar 

  12. Huygen K, Abramowicz D, Vandenbussche P, et al . Spleen cell cytokine secretion in Mycobacterium bovis BCG-infected mice Infect Immun. 60: 2880

  13. Sasaki H, Schmit D, Hayashi Y, Polland RB, Suzuki F . Induction of interleukin-3 and tumor resistance by SSM, a cancer immunotherapeutic agent extracted from Mycobacterium tuberculosis Cancer Res 1992 50: 4032–4037

    Google Scholar 

  14. Wallis RS, Amir-Tahmasseb M, Ellner JJ . Induction of interleukin 1 and tumor necrosis factor by mycobacterial proteins: the monocyte Western blot Proc Natl Acad Sci USA 1990 87: 3348–3352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boom WH, Wallis RS, Chervenak KA . Human Mycobacterium tuberculosis –reactive CD4 + T-cell clones: heterogeneity in antigen recognition, cytokine production, and cytotoxicity for mononuclear phagocytes Infect Immun 1992 59: 2737–2743

    Article  Google Scholar 

  16. Del Prete GF, De Carli M, Mastromauro C, et al . Purified protein derivative of Mycobacterium tuberculosis and excretory–secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production J Clin Invest 1993 88: 346–350

    Article  Google Scholar 

  17. Walker KB, Butler R, Colston MJ . Role of Th-1 lymphocytes in the development of protective immunity against Mycobacterium leprae Analysis of lymphocyte function by polymerase chain reaction detection of cytokine messenger RNA J Immunol 1992 148: 1885–1889

    CAS  PubMed  Google Scholar 

  18. Yoneda M, Fukui Y, Yamanouchi T . Extracellular proteins of tubercle bacilli: V. Distribution of α and β antigens in various mycobacteria Biken J 1988 8: 201–223

    Google Scholar 

  19. Hoffenbach A, Lagrane PH, Bach M-A . Starin variatio of lymphokine production and specific antibody secretion in mice infected with Mycobacterium lepraemurium Cell Immunol 1985 91: 1–11

    Article  CAS  PubMed  Google Scholar 

  20. Solowly MS . Intravesical and systemic chemotherapy of murine bladder cancer Cancer Res 1977 37: 2918–2924

    Google Scholar 

  21. Ikeda H, Ohta N, Furukawa K, et al . Mutated mitogen-activated protein kinase: a tumor rejection antigen of mouse sarcoma Proc Natl Acad Sci USA 1997 94: 6375–6379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Matsuo K, Yamaguchi R, Yamazaki A, et al . Cloning and expression of the gene for the cross-reactive alpha antigen of Mycobacterium kansasii Infect Immun 1990 58: 550–556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kitagawa S, Sato S, Hori S, et al . Induction of anti–allo-class I H-2 tolerance by inactivation of CD8 + helper T cell reversal of tolerance through introduction of third party helper T cells J Exp Med 1990 172: 105–113

    Article  CAS  PubMed  Google Scholar 

  24. Bruna-Romero O, Lasarte JJ, Wilkinson G, et al . Induction of cytotoxic T-cell response against hepatitis C virus structural antigens using a defective recombinant adenovirus Hepatology 1997 25: 470–477

    Article  CAS  PubMed  Google Scholar 

  25. Basker S . Gene-modified tumor cells as cellular vaccine Cancer Immunol Immunother 1996 43: 165–173

    Article  Google Scholar 

  26. Naerocki S, Mackieicz A . Genetically modified tumor vaccines — where we are today Cancer Treat Rev 1999 25: 29–46

    Article  Google Scholar 

  27. Shinkovics JG, Horvath JC . Vaccination against human cancers Int J Oncol 2000 16: 81–96

    Google Scholar 

  28. James RFL, Edwards S, Hui KM, et al . The effect of class II gene transfection on the tumorigenicity of the H-2k negative mouse leukemia cell line K36.16 Immunology. 1991 72: 213–218

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen PW, Ananthaswamy HN . Rejection of K1735 murine melanoma in syngenic hosts requires expression of major histocompatibility complex class I and either class II antigens or interleukin-2 J Immunol 1993 151: 244–255

    CAS  PubMed  Google Scholar 

  30. Rini BI, Selk LM, Vogelzang NJ . Phase I study of direct intralesional gene transfer of HLA-B7 into metastatic renal carcinoma lesions Clin Cancer Res 1999 5: 2766–2772

    CAS  PubMed  Google Scholar 

  31. Gleich LL . Gene therapy for head and neck cancer. Laryngoscope 2000 110: 708–762

    Article  CAS  PubMed  Google Scholar 

  32. Chen L, Ashe S, Brady W, et al . Costimulation of antitumor immunity by the B7 counter receptor for the T lymphocyte molecules CD28 and CTLA-4 Cell 1992 71: 1093–1102

    Article  CAS  PubMed  Google Scholar 

  33. Townsend SE, Allison JP . Tumor rejection after direct costimulation of CD8 + T cells by B7-transfected melanoma cells Science 1993 259: 368–370

    Article  CAS  PubMed  Google Scholar 

  34. Basker S, Ostrand-Rosenberg S, Nabavi N, et al . Constitutive expression of B7 restores the immunogenicity of tumor cells expressing truncated major histocompatibility complex class II molecules Proc Natl Acad Sci USA 1993 90: 5687–5690

    Article  Google Scholar 

  35. Li Y, McGowan P, Hellstrom I, et al . Costimulation of tumor-reactive CD4 + and CD8 + T lymphocytes by B7, natural ligand for CD28 can be used to treat established mouse melanoma J Immunol 1994 153: 421–428

    CAS  PubMed  Google Scholar 

  36. La Motte RN, Rubin MA, Barr E, et al . Therapeutic effectiveness of the immunity elicited by P815 tumor cells engineered to express the B7-2 costimulatory molecule. Cancer Immunol Immunother 1996 42: 161–169

    Article  CAS  PubMed  Google Scholar 

  37. Yang G, Hellstrom I, Hellstrom KE, et al . Antitumor immunity elicited by tumor cells transfected with B7-2, a second ligand for CD28/CTLA-4 costimulatory molecule J Immunol 1995 154: 2794–2800

    CAS  PubMed  Google Scholar 

  38. Gliboa E, Lyerly HK, Vieweg J, et al . Immunotherapy of cancer using cytokine gene-modified tumor vaccines Semin Cancer Biol 1994 5: 409–417

    Google Scholar 

  39. Abdel-Wahab Z, Weltz C, Hester D, et al . A phase I clinical trial of immunotherapy with IFN-γ gene–modified autologous melanoma cells Cancer, 1997 80: 401–412

    Article  CAS  Google Scholar 

  40. Belli F, Arienti F, Sule-Susuo J, et al . Active immunization of metastatic melanoma patients with interleukin-2–transduced allogenic melanoma cells: evaluation of efficacy and tolerability Cancer Immunol Immunother 1997 44: 197–203

    Article  CAS  PubMed  Google Scholar 

  41. Ellem KA, O'Rourke MG, Johnson GR, et al . A case report: immune responses and clinical course of the first human use of granulocyte/macrophage-colony-stimulating factor–transduced autologous melanoma cells for immunotherapy Cancer Immunol Immunother 1997 44: 10–20

    Article  CAS  PubMed  Google Scholar 

  42. Letvisky HI, Montgomery J, Ahmadzadeh M, et al . Immunization with granulocyte–macrophage colony-stimulating factor–transduced, but not B7-1 transduced, generates potent systemic antitumor immunity J Immunol 1996 156: 3858–3865

    Google Scholar 

  43. Fernandez NC, Levraud J-P, Haddada H, et al . High frequency of specific CD8 + T cells in the tumor and blood is associated with efficient local IL-12 gene therapy of cancer J Immunol 1999 162: 609–617

    CAS  PubMed  Google Scholar 

  44. Klein T, Nagai E, Ikubo A, et al . Granulocyte/macrophage-colony-stimulating factor released by adenovirally transduced CT26 cells leads to the local expression of macrophage inflammatory protein 1a and accumulation of dendritic cells at vaccination sites in vivo Cancer Immunol Immunother 1999 48: 123–131

    Article  Google Scholar 

  45. Rodolfo M, Zilocchi C, Cappetti B, et al . Cytotoxic T lymphocytes response against non-immunoselected tumor antigens predicts the outcome of gene therapy with IL-12–transduced tumor cell vaccine Gene Ther 1999 6: 865–872

    Article  CAS  PubMed  Google Scholar 

  46. Ali SA, Mclean CS, Boursnell MEG, et al . Preclinical evaluation of “whole” cell vaccines for prophylaxis and therapy using a disabled infectious single cycle-herpes simplex virus vector to transduce cytokine gene Cancer Res 2000 60: 1663–1670

    CAS  PubMed  Google Scholar 

  47. Cayeux S, Beck C, Aicher A, et al . Tumor cells cotransfected with interleukin-7 and B7.1 genes induce CD25 and CD28 on tumor-infiltrating T lymphocytes and are strong vaccine Eur J Immunol 1995 25: 2325–2331

    Article  CAS  PubMed  Google Scholar 

  48. Wakimoto H, Abe J, Tsunoda R, et al . Intensified antitumor immunity by a cancer vaccine that produces granulocyte–macrophage colony stimulating factor plus interleukin 4 Cancer Res 1996 56: 1828–1833

    CAS  PubMed  Google Scholar 

  49. Kato K, Okumura K, Yagita H . Immunoregulation by B7 and IL-12 gene transfer Leukemia 1997 11: 672–676

    Google Scholar 

  50. Kim TS, Chung SW, Hwang SY . Augmentation of antitumor immunity by genetically engineered fibroblast cells to express both B7.1 and interleukin-7 Vaccine, 2000 18: 2886–2894

    Article  CAS  Google Scholar 

  51. Chen SH, Chen XH, Wang Y, et al . Combination gene therapy for liver metastasis of colon carcinoma in vivo Proc Natl Acad Sci USA 1995 92: 2577–2581

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ratlif TL, Ritchey JK, Yuan JJ-J, et al . T-cell subsets required for intravesical BCG immunotherapy for bladder cancer J Urol 1993 150: 1018–1023

    Article  Google Scholar 

  53. McMaveny KM, Gomella LG, Lattime EC . Induction of TH1- and TH2-associated cytokine mRNA in mouse bladder following intravesical growth of the murine bladder tumor MB49 and BCG immunotherapy Cancer Immunol Immunother 1994 39: 401–406

    Article  Google Scholar 

  54. Thanhauser A, Bohle A, Schneider B, et al . The induction of bacillus-calmette-Guerin–activated killer cells requires the presence of monocytes and T-helper type-1 cells Cancer Immunol Immunother 1995 40: 103–108

    Article  CAS  PubMed  Google Scholar 

  55. Wiker HG, Harboe M . The antigen 85 complex: a major secretion product of Mycobacterium tuberculosis Microbiol Rev 1992 56: 648–661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Aung H, Tossi Z, Wisnieski JJ, et al . Induction of monocyte expression of tumor necrosis factor α by the 30-kD α antigen of Mycobacterium tuberculosis and synergism with fibronectin J Clin Invest 1996 98: 1261–1268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ohara N, Kitaura H, Hotokezaka H, et al . Characterization of the gene encoding the MPB51, one of the major secreted protein antigens of Mycobacterium bovis BCG, and identification of the secreted protein closely related to the fibronectin binding 85 complex Scand J Immunol 1995 41: 433–442

    Article  CAS  PubMed  Google Scholar 

  58. Naito M, Ohara N, Matsumoto S, et al . The novel fibronectin-binding motif and key residues of mycobacteria J Biol Chem 1998 273: 2905–2909

    Article  CAS  PubMed  Google Scholar 

  59. Martinez-Pineiro J, Martinez-Pineiro L . BCG update: intravesical therapy Eur Urol 1997 31: 31–41

    Article  CAS  PubMed  Google Scholar 

  60. Shirai M, Pendleton CD, Ahlers J, et al . Helper-CTL determinant linkage required for priming of anti-HIV CD8 + CTL in vivo with peptide vaccine constructs J Immunol 1994 152: 549–556

    CAS  PubMed  Google Scholar 

  61. Hiranuma K, Tamaki S, Nishimura Y, et al . Helper T cell determinant peptide contributes to induction of cellular immune responses by peptide vaccine against hepatitis C virus J Gen Virol 1999 80: 187–193

    Article  CAS  PubMed  Google Scholar 

  62. Macker HT, Uematsu DT, DeKruyff RH, et al . Cytotoxic T cell responses to DNA vaccination: dependence on antigen presentation via class II MHC J Immunol 1998 161: 6352–6536

    Google Scholar 

  63. Bennet SRM, Carbone FR, Karamalis F, et al . Help for cytotoxic-T-cell response is mediated by CD40 signaling Nature 1998 393: 478–480

    Article  CAS  Google Scholar 

  64. Ridge JP, Rosa FDi, Matzinger P . A conditional dendritic cell can be a temporal bridge between a CD4 + T-helper and a T-killer cell Nature 1998 393: 474–478

    Article  CAS  PubMed  Google Scholar 

  65. Schoenberger SP, Toes REM, van der Voort EIH, et al . T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions Nature 1998 393: 480–483

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants-in-Aid 1999 from the Mie Medical Research Foundation, Health Science Research Grants from the Ministry of Health, Labor and Welfare of Japan, and the Ministry of Education, Culture, Sports, Science and Technology of Japan..

Author information

Authors and Affiliations

  1. Department of Bioregulation, Mie University School of Medicine, Mie, 514-8507, Japan

    Isao Kuromatsu, Shiki Takamura, Gisen Kim & Yasuhiro Yasutomi

  2. Department of Urology, Mie University School of Medicine, Mie, 514-8507, Japan

    Isao Kuromatsu & Juichi Kawamura

  3. JST AIDS Vaccine Project, c/o National Institute of Health, Ministry of Public Health, Nonthaburi, 11000, Thailand

    Kazuhiro Matsuo

  4. Laboratory of Molecular Virology and Epidemiology, AIDS Research Center, National Institute of Infectious Disease, Tokyo, 108-8640, Japan

    Yutaka Takebe

Authors
  1. Isao Kuromatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuhiro Matsuo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shiki Takamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gisen Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yutaka Takebe
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Juichi Kawamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yasuhiro Yasutomi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasuhiro Yasutomi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kuromatsu, I., Matsuo, K., Takamura, S. et al. Induction of effective antitumor immune responses in a mouse bladder tumor model by using DNA of an α antigen from mycobacteria. Cancer Gene Ther 8, 483–490 (2001). https://doi.org/10.1038/sj.cgt.7700330

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.cgt.7700330

Keywords

This article is cited by

Search

Advanced search

Quick links