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.

  • Cell-Based Therapy
  • Published:

Cell-Based Therapy

Efficacy of cancer gene therapy in aging: adenocarcinoma cells engineered to release IL-2 are rejected but do not induce tumor specific immune memory in old mice

Abstract

Numerous studies have demonstrated the efficacy of cytokine gene-engineered tumor cells to induce tumor rejection and specific memory acquisition into syngeneic immunocompetent mice by activation of host-dependent antitumor responses. A progressive immune dysfunction, mainly involving thymus-dependent specific immunity, occurs during aging. In this study we evaluated whether the injection of IL-2 gene-transfected tumor cells in old mice causes an immune activation which results in tumor rejection and induction of specific immune memory as occurs in young animals. Young and old mice were inoculated with syngeneic parental mammary adenocarcinoma cells (TS/A p.c.) or with TS/A cells engineered to release IL-2 (TS/A-IL2). Three clones of TS/A-IL-2 cells were used producing low (30 U, B1.30), intermediate (3600 U, B6.3600), or high (6000 U, B4.6000) IL-2. While the B1.30 clone grew in 100% of mice, the B6.3600 and B4.6000 clones were promptly rejected in both young and old animals. In young mice, rejection was associated with a large neutrophil and macrophage infiltration, with a minor number of CD4+ and CD8+ lymphocytes. In old mice, neutrophils and macrophages were the main cells involved in tumor rejection whereas both CD4+ and CD8+ lymphocytes were scarcely present in tumoral infiltrate. A lower number of apoptotic tumor cells was found in TS/A-IL2-challenged old mice in comparison with young animals. To test whether the injection of TS/A-IL2 cells induced a specific immune memory, mice with no tumors after the challenge with B6.3600 and B4.6000 clones received a lethal challenge of TS/A p.c. 90% and 30% of young mice previously injected with B4.6000 or B6.3600 clones, respectively, rejected TS/A p.c. In old mice, B4.6000 cells did not confer protection, whereas only 10% of mice which received B6.3600 cells were able to reject TS/A p.c. Neither the graft of a young thymus or the adoptive transfer of young T lymphocytes to old mice induced specific immune memory for TS/A p.c. in old animals. These data suggest the necessity to refine antitumor vaccination procedures in aging.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Patel PM, Collins MKL . Gene therapy. In: Gore M, Riches P (eds) Immunotherapy in Cancer John Wiley: Chichester 1996 pp 221–234

    Google Scholar 

  2. Colombo MP, Forni G . Cytokine gene transfer in tumor inhibition and tumor therapy: where are we now? Immunol Today 1994 15: 48–51

    Article  CAS  Google Scholar 

  3. Dranoff G, Mulligan RC . Gene transfer as cancer therapy Adv Immunol 1995 58: 417–454

    Article  CAS  Google Scholar 

  4. Roth JA, Cristiano RJ . Gene therapy for cancer: what have we done and where are we going? J Natl Cancer Inst 1997 88: 21–39

    Article  Google Scholar 

  5. Musiani P et al. Cytokines, tumor-cell death and immunogenicity: a question of choice Immunol Today 1997 18: 32–36

    Article  CAS  Google Scholar 

  6. Cavallo F et al. Protective and curative potential with interleukin-2-gene-transfected cells from a spontaneous mouse mammary adenocarcinoma Cancer Res 1993 53: 5067–5070

    CAS  Google Scholar 

  7. Cavallo F et al. Antitumor efficacy of adenocarcinoma cells engineered to produce interleukin-12 (IL-12) or other cytokines compared with exogenous IL-12 J Natl Cancer Inst 1997 89: 1049–1058

    Article  CAS  Google Scholar 

  8. Cavallo F et al. Role of neutrophils and CD4+ T lymphocytes in the mammary and memory response to nonimmunogenic murine mammary adenocarcinoma made immunogenic by IL-2 gene J Immunol 1992 149: 3627–3635

    CAS  Google Scholar 

  9. Miller RA . The aging immune system: primer and prospectus Science 1996 273: 70–74

    Article  CAS  Google Scholar 

  10. Fabris N, Mocchegiani E, Provinciali M . Plasticity of neuro-endocrine–thymus interactions during aging Exp Gerontol 1997 32: 415–430

    Article  CAS  Google Scholar 

  11. Pawelec G, Solana R . Immunosenescence Immunol Today 1997 18: 514–516

    Article  CAS  Google Scholar 

  12. George AJT, Ritter MA . Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today 1996 17: 267–272

    Article  CAS  Google Scholar 

  13. Thoman ML, Weigle WO . The cellular and subcellular bases of immunosenescence Adv Immunol 1989 46: 221–261

    Article  CAS  Google Scholar 

  14. Proust JJ, Bender BS, Nagel JE, Adler WH . Developmental biology and senescence. In: Nelson DS (ed) Natural Immunity Academic Press: Australia 1989 pp 392–439

    Google Scholar 

  15. Provinciali M, Di Stefano G, Fabris N . Evaluation of LAK cell development in young and old healthy humans Nat Immunity 1995 14: 134–144

    CAS  Google Scholar 

  16. Provinciali M, Di Stefano G, Stronati S, Fabris N . Generation of human lymphokine-activated killer cells following an IL-2 pulse in elderly cancer patients Cytokine 1998 10: 132–139

    Article  CAS  Google Scholar 

  17. Rosen ST, Benson III AB, Kuzel T, Tallman MS . Biologic therapies in cancer patients: inplications for treatment in older patients. In: Balducci L, Lyman GH, Ershler WB (eds) Geriatric Oncology Lippincott: Philadelphia 1992 pp 181–189

    Google Scholar 

  18. Smith KA . Interleukin-2 Ann Rev Immunol 1984 2: 319–335

    Article  CAS  Google Scholar 

  19. Henney CS, Kuribayashi DE, Kern E, Gillis S . Interleukin-2 augments natural killer activity Nature 1981 291: 335–338

    Article  CAS  Google Scholar 

  20. Grimm EA, Rosenberg SA . The human lymphokine activated killer cell phenomenon Lymphokines 1983 9: 435–438

    Google Scholar 

  21. Espinoza-Delgado I et al. Expression and role of p75 interleukin 2 receptor on human monocytes J Exp Med 1990 171: 1821–1826

    Article  CAS  Google Scholar 

  22. Phalavani MA, Richardson AR . The effect of age on the expression of interleukin-2 Mech Ageing Dev 1996 89: 125–154

    Article  Google Scholar 

  23. Provinciali M et al. Adjuvant effect of low-dose interleukin-2 on antibody response to influenza virus vaccination in healthy elderly subjects Mech Ageing Dev 1994 77: 75–82

    Article  CAS  Google Scholar 

  24. Saini A, Sei Y . Age-related impairment of early and late events of signal transduction in mouse immune cells Life Sci 1993 52: 1759–1765

    Article  CAS  Google Scholar 

  25. Herndon FJ, Hsu HI, Mountz JD . Increased apoptosis of CD45RO T cells with aging Mech Ageing Dev 1997 94: 123–134

    Article  CAS  Google Scholar 

  26. Hirokawa K, Utsuyama M . The effect of sequential multiple grafting of syngeneic newborn thymus on the immune functions and life expectancy of aging mice Mech Ageing Dev 1984 28: 111–121

    Article  CAS  Google Scholar 

  27. Butenko GM, Kharazi AI . Effect of thymus grafts of various ages on the immune system formation in CBA mice Mech Ageing Dev 1985 30: 227–237

    Article  CAS  Google Scholar 

  28. Garg M, Luo W, Kaplan AM, Bondada S . Cellular basis of decreased immune responses to pneumococcical vaccines in aged mice Infect Immun 1996 64: 4456–4462

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Vetvicka V, Tlaskalova-Hogenova H, Pospisil M . Impaired antigen presenting function of macrophages from aged mice Immunol Invest 1985 14: 105–114

    Article  CAS  Google Scholar 

  30. Albert ML, Sauter B, Bahrdwaj N . Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs Nature 1998 392: 86–89

    Article  CAS  Google Scholar 

  31. Henry F et al. Antigen-presenting cells that phagocytose apoptotic tumor-derived cells are potent tumor vaccines Cancer Res 1999 59: 3329–3332

    CAS  Google Scholar 

  32. Nanni P et al. TS/A: a new metastasizing cell line from a BALB/c spontaneous mammary adenocarcinoma Clin Exp Metast 1983 1: 373–380

    Article  CAS  Google Scholar 

  33. Bryant J, Day R, Whitside T, Herberman RB . Calculation of lytic units for the expression of cell-mediated cytotoxicity J Immunol Meth 1992 146: 91–103

    Article  CAS  Google Scholar 

  34. Basso A, Piantanelli L, Rossolini G, Roth GS . Reduced DNA synthesis in primary cultures of hepatocytes from old mice is restored by thymus grafts J Gerontol 1998 53A: B111–B116

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ms Beatrice Bartozzi, Ms Grazia Di Stasio and Mr Giovanni Bernardini for their excellent technical assistance.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Provinciali, M., Argentati, K. & Tibaldi, A. Efficacy of cancer gene therapy in aging: adenocarcinoma cells engineered to release IL-2 are rejected but do not induce tumor specific immune memory in old mice. Gene Ther 7, 624–632 (2000). https://doi.org/10.1038/sj.gt.3301131

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301131

Keywords

This article is cited by

Search

Quick links