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.

Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance

Nature volume 437, pages 141–146 (2005)Cite this article

Abstract

The recognition and elimination of tumours by T cells, a process termed cancer immunosurveillance1, is effective against certain virus-associated cancers2. Spontaneous tumours often induce a specific immune response and are therefore also immunogenic. However, it is not clear whether they can be controlled by T cells3,4,5,6,7,8,9,10. The immunosurveillance hypothesis postulates that tumours, if they eventually grow, escaped T-cell recognition by losing immunogenicity6,7,8. Here we show, by generating a mouse model of sporadic cancer based on rare spontaneous activation of a dormant oncogene, that immunogenic tumours do not escape their recognition but induce tolerance. In this model, tumours derive from single cells and express a tumour-specific transplantation rejection antigen. Whereas vaccinated mice remain tumour-free throughout their lifetime, naive mice always develop a progressively growing tumour. We also show that despite specific recognition by T cells, the tumours do not lose their intrinsic immunogenicity and are rejected after transplantation in T-cell-competent recipients. Furthermore, in the primary host tumour-induced tolerance is associated with the expansion of non-functional T cells. Together, our data argue against immunosurveillance of spontaneous cancer.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: LoxP-Tag transgenic mice develop sporadic tumours as a result of rare epigenetic or genetic events.
Figure 2: LoxP-Tag mice are not tolerant towards Tag and control sporadic and Cre-recombinase-induced tumours after immunization.
Figure 3: Sporadic immunogenic LoxP-Tag tumours induce a Tag-specific immune response.
Figure 4: Sporadic immunogenic tumours induce T-cell tolerance.

References

  1. Burnet, M. Immunological factors in the process of carcinogenesis. Br. Med. Bull. 20, 154–158 (1964)

    Article  CAS  PubMed  Google Scholar 

  2. Klein, G. & Klein, E. Immune surveillance against virus-induced tumors and nonrejectability of spontaneous tumors: contrasting consequences of host versus tumour evolution. Proc. Natl Acad. Sci. USA 74, 2121–2125 (1977)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Stutman, O. Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Science 183, 534–536 (1974)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Prehn, R. T. Stimulatory effects of immune reactions upon the growths of untransplanted tumors. Cancer Res. 54, 908–914 (1994)

    CAS  PubMed  Google Scholar 

  5. Klein, G., Sjogren, H. O., Klein, E. & Hellstrom, K. E. Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host. Cancer Res. 20, 1561–1572 (1960)

    CAS  PubMed  Google Scholar 

  6. Shankaran, V. et al. IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410, 1107–1111 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  7. Street, S. E., Trapani, J. A., MacGregor, D. & Smyth, M. J. Suppression of lymphoma and epithelial malignancies effected by interferon gamma. J. Exp. Med. 196, 129–134 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumour escape. Nature Immunol. 3, 991–998 (2002)

    Article  CAS  Google Scholar 

  9. Blankenstein, T. & Qin, Z. Chemical carcinogens as foreign bodies and some pitfalls regarding cancer immune surveillance. Adv. Cancer Res. 90, 179–207 (2003)

    Article  CAS  PubMed  Google Scholar 

  10. Qin, Z. & Blankenstein, T. A cancer immunosurveillance controversy. Nature Immunol. 5, 3–4 (2004)

    Article  CAS  Google Scholar 

  11. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  12. Meuwissen, R., Jonkers, J. & Berns, A. Mouse models for sporadic cancer. Exp. Cell Res. 264, 100–110 (2001)

    Article  CAS  PubMed  Google Scholar 

  13. Adams, T. E., Alpert, S. & Hanahan, D. Non-tolerance and autoantibodies to a transgenic self antigen expressed in pancreatic beta cells. Nature 325, 223–228 (1987)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Schell, T. D., Knowles, B. B. & Tevethia, S. S. Sequential loss of cytotoxic T lymphocyte responses to simian virus 40 large T antigen epitopes in T antigen transgenic mice developing osteosarcomas. Cancer Res. 60, 3002–3012 (2000)

    CAS  PubMed  Google Scholar 

  15. Mullen, C. A., Urban, J. L., Van Waes, C., Rowley, D. A. & Schreiber, H. Multiple cancers. Tumor burden permits the outgrowth of other cancers. J. Exp. Med. 162, 1665–1682 (1985)

    Article  CAS  PubMed  Google Scholar 

  16. Beck, C., Schreiber, H. & Rowley, D. Role of TGF-beta in immune-evasion of cancer. Microsc. Res. Tech. 52, 387–395 (2001)

    Article  CAS  PubMed  Google Scholar 

  17. Gorelik, L. & Flavell, R. A. Transforming growth factor-beta in T-cell biology. Nature Rev. Immunol. 2, 46–53 (2002)

    Article  CAS  Google Scholar 

  18. Enzler, T. et al. Deficiencies of GM-CSF and interferon gamma link inflammation and cancer. J. Exp. Med. 197, 1213–1219 (2003)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Khong, H. T. & Restifo, N. P. Natural selection of tumour variants in the generation of ‘tumour escape’ phenotypes. Nature Immunol. 3, 999–1005 (2002)

    Article  CAS  Google Scholar 

  20. Schreiber, H. in Fundamental Immunology 5th edn (ed. Paul, W.) 1557–1592 (Raven, Philadelphia, 2003)

    Google Scholar 

  21. Staveley-O'Carroll, K. et al. Induction of antigen-specific T cell anergy: An early event in the course of tumour progression. Proc. Natl Acad. Sci. USA 95, 1178–1183 (1998)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee, P. P. et al. Characterization of circulating T cells specific for tumour-associated antigens in melanoma patients. Nature Med. 5, 677–685 (1999)

    Article  CAS  PubMed  Google Scholar 

  23. Blankenstein, T. The role of tumour stroma in the interaction between tumour and immune system. Curr. Opin. Immunol. 17, 180–186 (2005)

    Article  CAS  PubMed  Google Scholar 

  24. van Mierlo, G. J. et al. Activation of dendritic cells that cross-present tumour-derived antigen licenses CD8+ CTL to cause tumour eradication. J. Immunol. 173, 6753–6759 (2004)

    Article  CAS  PubMed  Google Scholar 

  25. Old, L. J., Boyse, E. A., Clarke, D. A. & Carswell, E. A. Antigenic properties of chemically-induced tumors. Ann. NY Acad. Sci. 101, 80–106 (1962)

    Article  ADS  CAS  Google Scholar 

  26. Kripke, M. L. & Fisher, M. S. Immunologic parameters of ultraviolet carcinogenesis. J. Natl. Cancer Inst. 57, 211–215 (1976)

    Article  CAS  PubMed  Google Scholar 

  27. Sakai, K., Mitani, K. & Miyazaki, J. Efficient regulation of gene expression by adenovirus vector-mediated delivery of the CRE recombinase. Biochem. Biophys. Res. Commun. 217, 393–401 (1995)

    Article  CAS  PubMed  Google Scholar 

  28. Li, L. P., Schlag, P. M. & Blankenstein, T. Transient expression of SV 40 large T antigen by Cre/LoxP-mediated site- specific deletion in primary human tumour cells. Hum. Gene Ther. 8, 1695–1700 (1997)

    Article  CAS  PubMed  Google Scholar 

  29. Cayeux, S., Richter, G., Noffz, G., Dörken, B. & Blankenstein, T. Influence of gene-modified (IL-7, IL-4, and B7) tumour cell vaccines on tumour antigen presentation. J. Immunol. 158, 2834–2841 (1997)

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S. Horn, D. Barthel, C. Westen, A. Gaertner and M. Roesch for technical assistance; M. Czéh and T. Kammertoens for discussion; and N. Karamatskos for statistical analysis. This work was supported by grants from the Deutsche Forschungsgemeinschaft and the Deutsche Krebshilfe, Dr Mildred Scheel-Stiftung.

Author information

Authors and Affiliations

  1. Institute of Immunology, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany

    Gerald Willimsky & Thomas Blankenstein

  2. Max Delbrück Center for Molecular Medicine, Robert-Roessle Strasse 10, 13122, Berlin, Germany

    Thomas Blankenstein

Authors
  1. Gerald Willimsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Blankenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Blankenstein.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Figure Legends

Text to accomapany the below Supplementary Figures. (PDF 33 kb)

Supplementary Figure S1

Flow cytometric analysis of two representative tumour cell lines by staining with cytokeratin or CD11b specific mAb. (PDF 89 kb)

Supplementary Figure S2

Tumour cell lines with bicistronic mRNA show CAT activity, those with spontaneous attenuator deletion do not. (PDF 46 kb)

Supplementary Figure S3

CD8+ and CD4+ T cells infiltrate spontaneous tumours in LoxP-Tag transgenic mice. (PDF 119 kb)

Supplementary Figure S4

Sporadic tumours of LoxP-Tag mice are highly immunogenic due to Tag expression. (PDF 58 kb)

Supplementary Figure S5

Tumour bearing LoxP-Tag mice cannot kill Tag-peptide loaded spleen cells. (PDF 162 kb)

Supplementary Figure S6

The aged LoxP-Tag mice that are shown in Fig. 4b were analyzed for Tag-specific IgG antibodies in the blood before 16.113 tumour challenge. (PDF 62 kb)

Supplementary Figure S7

LoxP-Tag transgenic mice develop Tag-specific antibodies predominantly of IgG2a, IgG2b and occasionally IgA subtypes upon tumour development. (PDF 71 kb)

Supplementary Figure S8

Lack of IFN-γ slightly shortens tumour latency in part of the mice but did not increase tumour incidence. (PDF 50 kb)

Supplementary Figure S9

Tumour cells in most cases do not produce TGF-β1. (PDF 51 kb)

Supplementary Table S1

Tumours from LoxP-Tag mice are highly immunogenic. (PDF 40 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Willimsky, G., Blankenstein, T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437, 141–146 (2005). https://doi.org/10.1038/nature03954

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03954

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing