Letter | Published:

Adaptive immunity maintains occult cancer in an equilibrium state

Nature volume 450, pages 903907 (06 December 2007) | Download Citation


The capacity of immunity to control and shape cancer, that is, cancer immunoediting, is the result of three processes1,2,3,4,5,6,7,8 that function either independently or in sequence9: elimination (cancer immunosurveillance, in which immunity functions as an extrinsic tumour suppressor in naive hosts); equilibrium (expansion of transformed cells is held in check by immunity); and escape (tumour cell variants with dampened immunogenicity or the capacity to attenuate immune responses grow into clinically apparent cancers). Extensive experimental support now exists for the elimination and escape processes because immunodeficient mice develop more carcinogen-induced and spontaneous cancers than wild-type mice, and tumour cells from immunodeficient mice are more immunogenic than those from immunocompetent mice. In contrast, the equilibrium process was inferred largely from clinical observations, including reports of transplantation of undetected (occult) cancer from organ donor into immunosuppressed recipients10. Herein we use a mouse model of primary chemical carcinogenesis and demonstrate that equilibrium occurs, is mechanistically distinguishable from elimination and escape, and that neoplastic cells in equilibrium are transformed but proliferate poorly in vivo. We also show that tumour cells in equilibrium are unedited but become edited when they spontaneously escape immune control and grow into clinically apparent tumours. These results reveal that, in addition to destroying tumour cells and sculpting tumour immunogenicity, the immune system of a naive mouse can also restrain cancer growth for extended time periods.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

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

  2. 2.

    , , , & Cancer immunoediting: from immunosurveillance to tumor escape. Nature Immunol. 3, 991–998 (2002)

  3. 3.

    , , & Suppression of lymphoma and epithelial malignancies effected by interferon γ. J. Exp. Med. 196, 129–134 (2002)

  4. 4.

    et al. NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J. Exp. Med. 200, 1325–1335 (2004)

  5. 5.

    , & The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148 (2004)

  6. 6.

    et al. A critical function for type I interferons in cancer immunoediting. Nature Immunol. 6, 722–729 (2005)

  7. 7.

    , & The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004)

  8. 8.

    , & Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv. Immunol. 90, 1–50 (2006)

  9. 9.

    , & Interferons, immunity and cancer immunoediting. Nature Rev. Immunol. 6, 836–848 (2006)

  10. 10.

    , & Fatal melanoma transferred in a donated kidney 16 years after melanoma surgery. N. Engl. J. Med. 348, 567–568 (2003)

  11. 11.

    , , & Inhibition of methylcholanthrene-induced carcinogenesis by an interferon γ receptor-dependent foreign body reaction. J. Exp. Med. 195, 1479–1490 (2002)

  12. 12.

    & Ki67 protein: the immaculate deception? Histopathology 40, 2–11 (2002)

  13. 13.

    et al. Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells. J. Cell. Physiol. 206, 624–635 (2006)

  14. 14.

    , & Tumour-dormant states established with L5178Y lymphoma cells in immunised syngeneic murine hosts. Nature 270, 59–61 (1977)

  15. 15.

    , , & Tumor dormancy. I. Regression of BCL1 tumor and induction of a dormant tumor state in mice chimeric at the major histocompatibility complex. J. Immunol. 137, 1376–1382 (1986)

  16. 16.

    et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006)

  17. 17.

    Focus on TILs: Prognostic significance of tumor infiltrating lymphocytes in human colorectal cancer. Cancer Immun. 7, 4–12 (2007)

  18. 18.

    et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl Acad. Sci. USA 102, 18538–18543 (2005)

  19. 19.

    & Histological markers of risk and the role of high-grade prostatic intraepithelial neoplasia. Urology 57, 115–120 (2001)

  20. 20.

    & Using autopsy series to estimate the disease “reservoir” for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann. Intern. Med. 127, 1023–1028 (1997)

  21. 21.

    et al. Molecular identification of latent precancers in histologically normal endometrium. Cancer Res. 61, 4311–4314 (2001)

  22. 22.

    et al. Computed tomography screening and lung cancer outcomes. J. Am. Med. Assoc. 297, 953–961 (2007)

  23. 23.

    & Cancer: an inflammatory link. Nature 431, 405–406 (2004)

  24. 24.

    & A cytokine-mediated link between innate immunity, inflammation, and cancer. J. Clin. Invest. 117, 1175–1183 (2007)

  25. 25.

    et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 191, 661–668 (2000)

  26. 26.

    et al. Characterization of the murine antigenic determinant, designated L3T4a, recognized by monoclonal antibody GK1.5: expression of L3T4a by functional T cell clones appears to correlate primarily with class II MHC antigen-reactivity. Immunol. Rev. 74, 29–56 (1983)

  27. 27.

    , , , & Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 312, 548–551 (1984)

  28. 28.

    , , , & Monoclonal antibodies to murine γ-interferon which differentially modulate macrophage activation and antiviral activity. J. Immunol. 134, 1609–1618 (1985)

  29. 29.

    et al. Costimulation of multiple NK cell activation receptors by NKG2D. J. Immunol. 169, 3667–3675 (2002)

  30. 30.

    & Establishment of monoclonal anti-Nk-1.1 antibody. Hybridoma 3, 301–303 (1984)

  31. 31.

    et al. Expression and function of TNF-related apoptosis-inducing ligand on murine activated NK cells. J. Immunol. 163, 1906–1913 (1999)

  32. 32.

    et al. Interleukin-12 is required for interferon-γ production and lethality in lipopolysaccharide-induced shock in mice. Eur. J. Immunol. 25, 672–676 (1995)

  33. 33.

    et al. A critical function for type I interferons in cancer immunoediting. Nature Immunol. 6, 722–729 (2005)

  34. 34.

    et al. Differential tumor surveillance by natural killer (NK) and NKT cells. J. Exp. Med. 4, 661–668 (2000)

  35. 35.

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

Download references


The authors are grateful for the advice of E. Unanue, G. Dunn, H. Virgin, P. Allen, M. Colonna, J. Trapani, R. Uppaluri, J. Bui and all members of the Schreiber laboratory during the preparation of this manuscript. We also greatly appreciate the technical assistance of C. Arthur, M. White, J. Archambault and J. Sharkey. This work was supported by grants to R.D.S. from the National Cancer Institute, the Ludwig Institute for Cancer Research, the Cancer Research Institute and Atlantic Philanthropies, and to M.J.S. from the National Health and Medical Research Council of Australia for Fellowship and Program Grant Support. C.M.K. was supported by a pre-doctoral training grant from the Cancer Research Institute. J.B.S. was supported by an Australian Postgraduate Research Award.

Author Contributions The work in this paper reflects an equal contribution from the M.J.S and R.D.S. laboratories. C.M.K., M.J.S. and R.D.S. were involved in all aspects of experimental work, project planning and data analysis. W.V. and S.J.R. were responsible for performing and interpreting the histological analyses. L.J.O. and J.B.S. participated in project planning and N.Z. was involved in the experimental work.

Author information

Author notes

    • Mark J. Smyth
    •  & Robert D. Schreiber

    These authors contributed equally to this work.


  1. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA

    • Catherine M. Koebel
    • , William Vermi
    •  & Robert D. Schreiber
  2. Department of Pathology, University of Brescia/Spedali Civili di Brescia, Brescia 25123, Italy

    • William Vermi
  3. Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia

    • Jeremy B. Swann
    • , Nadeen Zerafa
    •  & Mark J. Smyth
  4. Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia

    • Jeremy B. Swann
    •  & Mark J. Smyth
  5. Department of Pathology, Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts 02115, USA

    • Scott J. Rodig
  6. Ludwig Institute for Cancer Research at Memorial Sloan Kettering Cancer Center, New York 10021, USA

    • Lloyd J. Old


  1. Search for Catherine M. Koebel in:

  2. Search for William Vermi in:

  3. Search for Jeremy B. Swann in:

  4. Search for Nadeen Zerafa in:

  5. Search for Scott J. Rodig in:

  6. Search for Lloyd J. Old in:

  7. Search for Mark J. Smyth in:

  8. Search for Robert D. Schreiber in:

Corresponding authors

Correspondence to Mark J. Smyth or Robert D. Schreiber.

Supplementary information

PDF files

  1. 1.

    Supplementary Figures

    The file contains Supplementary Figures S1-S4 with Legends.

About this article

Publication history






Further reading


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.