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.

  • Review Article
  • Published:

Cancer despite immunosurveillance: immunoselection and immunosubversion

Nature Reviews Immunology volume 6, pages 715–727 (2006)Cite this article

Key Points

  • The concept of immunosurveillance implies that the immune system can recognize and destroy most precursors of cancer. Cancer cells avoid immunosurveillance by the selection of non-immunogenic tumour-cell variants (which is known as immunoselection) and by the active suppression of the immune response (which is known as immunosubversion).

  • The development of cancer is inhibited by several mechanisms that suppress tumours, many of which function in a cell-intrinsic manner. The activation of oncogenes can trigger the DNA-damage response, which controls pre-malignant lesions through the activation of several types of molecule: DNA-damage sensors, such as ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3 related); checkpoint kinases, such as CHK1 (checkpoint kinase 1 homologue) and CHK2; and the tumour-suppressor protein p53. ATM, ATR and CHK2 can also induce the expression of ligands for NKG2D (natural-killer group 2, member D) by tumour cells, thereby activating a cytotoxic response by NKG2D-expressing lymphocytes involved in immunosurveillance.

  • Cancers have six recognized hallmarks, each of which influences the immunological characteristics of tumour cells. First, tumours can become self-sufficient for growth signals by producing autocrine and paracrine growth factors that have immunosuppressive characteristics. Second, tumours become insensitive to antigrowth signals (such as transforming growth factor-β), which induce local immunosuppression. Third, tumours evade apoptosis by overexpressing mitochondrial cell-death inhibitors (which are potential tumour antigens) and avoid caspase activation (which is required for immunogenic cell death). Fourth, limitless replication is associated with overexpression of TERT (telomerase reverse transcriptase) and mutation of p53, two potential tumour antigens. Fifth, sustained angiogenesis involves tumour production of angiogenic factors, such as vascular endothelial growth factor, that inhibit dendritic-cell maturation and T-cell activation. Sixth, local invasion and metastasis are also associated with beneficial and deleterious changes in the immunological characteristics of tumours.

  • We favour the existence of a seventh, partly independent, hallmark of cancer, as has previously been proposed by other researchers. This hallmark is the avoidance of immune recognition by alteration of tumour-cell characteristics, as well as by creation of a local immunosuppressive network that inactivates innate and adaptive cytolytic effectors.

  • Immunoselection is likely to have the main role in the early stages of carcinogenesis, whereas immunosubversion gradually accompanies advancing tumour growth, although there might be exceptions to this.

  • The complete and permanent success of anticancer therapy relies on the induction of a productive immune response that eliminates residual tumour cells that have survived chemotherapy or radiotherapy. Immunostimulatory strategies that are designed to counter immunosubversion will be crucial for the development of an immunogenic chemotherapeutic regimen. Some current chemotherapeutic regimens have immunostimulatory effects, perhaps partly explaining their antitumour efficacy.

Abstract

Numerous innate and adaptive immune effector cells and molecules participate in the recognition and destruction of cancer cells, a process that is known as cancer immunosurveillance. But cancer cells avoid such immunosurveillance through the outgrowth of poorly immunogenic tumour-cell variants (immunoselection) and through subversion of the immune system (immunosubversion). At the early stages of carcinogenesis, cell-intrinsic barriers to tumour development seem to be associated with stimulation of an active antitumour immune response, whereas overt tumour development seems to correlate with changes in the immunogenic properties of tumour cells. The permanent success of treatments for cancer might depend on using immunogenic chemotherapy to re-establish antitumour immune responses.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Relationship between cell-intrinsic and cell-extrinsic aspects of tumour progression.
Figure 2: Cancer immunosurveillance.
Figure 3: Hypothetical links between endogenous tumour suppression and immunosurveillance.
Figure 4: Mechanisms of tumour escape from the immune system.

Similar content being viewed by others

References

  1. Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000). This landmark review was the first to enumerate systematically the cell-intrinsic characteristics of cancer cells.

    CAS  PubMed  Google Scholar 

  2. Dunn, G. P., Old, L. J. & Schreiber, R. D. The three Es of cancer immunoediting. Annu. Rev. Immunol. 22, 329–360 (2004). This was the first paper to propose that avoidance of immunosurveillance could be the seventh hallmark of cancer.

    CAS  PubMed  Google Scholar 

  3. Smyth, M. J., Dunn, G. P. & Schreiber, R. D. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv. Immunol. 90, 1–50 (2006).

    CAS  PubMed  Google Scholar 

  4. Dunn, G. P., Old, L. J. & Schreiber, R. D. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21, 137–148 (2004). This paper brilliantly summarizes the concept of immunoediting.

    CAS  PubMed  Google Scholar 

  5. Billiau, A. et al. Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-γ. J. Immunol. 140, 1506–1510 (1988).

    CAS  PubMed  Google Scholar 

  6. Takeda, K. et al. Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development. J. Exp. Med. 195, 161–169 (2002). A pioneering study that underscores the role of TRAIL in cancer immunosurveillance.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Raulet, D. H. Roles of the NKG2D immunoreceptor and its ligands. Nature Rev. Immunol. 3, 781–790 (2003).

    CAS  Google Scholar 

  8. Smyth, M. J. et al. Sequential activation of NKT cells and NK cells provides effective innate immunotherapy of cancer. J. Exp. Med. 201, 1973–1985 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Taieb, J. et al. A novel dendritic cell subset involved in tumor immunosurveillance. Nature Med. 12, 214–219 (2006).

    CAS  PubMed  Google Scholar 

  10. Dhodapkar, M. V., Krasovsky, J., Osman, K. & Geller, M. D. Vigorous premalignancy-specific effector T cell response in the bone marrow of patients with monoclonal gammopathy. J. Exp. Med. 198, 1753–1757 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Beckhove, P. et al. Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors. J. Clin. Invest. 114, 67–76 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schmitz-Winnenthal, F. H. et al. High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients. Cancer Res. 65, 10079–10087 (2005).

    CAS  PubMed  Google Scholar 

  13. Willimsky, G. & Blankenstein, T. Sporadic immunogenic tumours avoid destruction by inducing T-cell tolerance. Nature 437, 141–146 (2005). An elegant study showing that immunoediting might not occur for spontaneously arising tumours that overexpress simian virus 40 (SV40).

    CAS  PubMed  Google Scholar 

  14. Wang, X. et al. Autoantibody signatures in prostate cancer. N. Engl. J. Med. 353, 1224–1235 (2005).

    CAS  PubMed  Google Scholar 

  15. Suzuki, H., Graziano, D. F., McKolanis, J. & Finn, O. J. T cell-dependent antibody responses against aberrantly expressed cyclin B1 protein in patients with cancer and premalignant disease. Clin. Cancer Res. 11, 1521–1526 (2005).

    CAS  PubMed  Google Scholar 

  16. Li, Y. et al. p53 autoantibodies predict subsequent development of cancer. Int. J. Cancer 114, 157–160 (2005).

    CAS  PubMed  Google Scholar 

  17. Egloff, A. M., Weissfeld, J., Land, S. R. & Finn, O. J. Evaluation of anticyclin B1 serum antibody as a diagnostic and prognostic biomarker for lung cancer. Ann. NY Acad. Sci. 1062, 29–40 (2005).

    CAS  PubMed  Google Scholar 

  18. Zitvogel, L., Casares, N., Pequignot, M., Albert, M. L. & Kroemer, G. The immune response against dying tumor cells. Adv. Immunol. 84, 131–179 (2004).

    CAS  PubMed  Google Scholar 

  19. Pages, F. et al. Epstein–Barr virus nuclear antigen 2 induces interleukin-18 receptor expression in B cells. Blood 105, 1632–1639 (2005).

    CAS  PubMed  Google Scholar 

  20. Nakamura, E. et al. Genetic polymorphisms of the interleukin-4 receptor α gene are associated with an increasing risk and a poor prognosis of sporadic renal cell carcinoma in a Japanese population. Clin. Cancer Res. 8, 2620–2625 (2002).

    CAS  PubMed  Google Scholar 

  21. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–949 (2004).

    CAS  PubMed  Google Scholar 

  22. Viguier, M. et al. Foxp3 expressing CD4+CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J. Immunol. 173, 1444–1453 (2004).

    CAS  PubMed  Google Scholar 

  23. Ghiringhelli, F. et al. CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor-β-dependent manner. J. Exp. Med. 202, 1075–1085 (2005). References 21–23 provide strong evidence of a role for T Reg cells in tumour-induced tolerance.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Bronte, V. et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J. Exp. Med. 201, 1257–1268 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Penn, I. Post-transplant malignancy: the role of immunosuppression. Drug Saf. 23, 101–113 (2000).

    CAS  PubMed  Google Scholar 

  26. Hollenbeak, C. S. et al. Increased incidence of melanoma in renal transplantation recipients. Cancer 104, 1962–1967 (2005).

    PubMed  Google Scholar 

  27. Kobayashi, N. Malignant neoplasms in registered cases of primary immunodeficiency syndrome. Jpn J. Clin. Oncol. 15 (Suppl. 1), 307–312 (1985).

    PubMed  Google Scholar 

  28. Clementi, R. et al. A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood 105, 4424–4428 (2005).

    CAS  PubMed  Google Scholar 

  29. Sun, T. et al. FASL-844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer. J. Exp. Med. 202, 967–974 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Carrington, M. et al. Hierarchy of resistance to cervical neoplasia mediated by combinations of killer immunoglobulin-like receptor and human leukocyte antigen loci. J. Exp. Med. 201, 1069–1075 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Nakachi, K., Hayashi, T., Imai, K. & Kusunoki, Y. Perspectives on cancer immuno-epidemiology. Cancer Sci. 95, 921–929 (2004).

    CAS  PubMed  Google Scholar 

  32. Imai, K., Matsuyama, S., Miyake, S., Suga, K. & Nakachi, K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet 356, 1795–1799 (2000).

    CAS  PubMed  Google Scholar 

  33. Hayashi, T. et al. Identification of the NKG2D haplotypes associated with natural cytotoxic activity of peripheral blood lymphocytes and cancer immunosurveillance. Cancer Res. 66, 563–570 (2006). References 31–33 introduce the novel concept of two hits for cancer development: first, the oncogenic event that leads to cell-surface expression of stress-associated molecules; and second, the recognition of these molecules by innate immune cells that display receptors with a polymorphism that allows tumour escape.

    CAS  PubMed  Google Scholar 

  34. Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004).

    CAS  PubMed  Google Scholar 

  35. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    CAS  PubMed  Google Scholar 

  36. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005). References 35 and 36 underscore the importance of the oncogene-induced ATM–CHK1–p53 pathway in the control of early pre-malignant lesions as a mechanism of tumour suppression.

    CAS  PubMed  Google Scholar 

  37. Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005). This seminal study provided the first indication that the DNA-damage response induced by endogenous stress (in this case, oncogene activation) or therapy is linked to the induction of expression of 'danger' signals.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Smyth, M. J. et al. NKG2D function protects the host from tumor initiation. J. Exp. Med. 202, 583–588 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhou, H. et al. DNA-based vaccines activate innate and adaptive antitumor immunity by engaging the NKG2D receptor. Proc. Natl Acad. Sci. USA 102, 10846–10851 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Watson, N. F. et al. Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int. J. Cancer 118, 1445–1452 (2006).

    CAS  PubMed  Google Scholar 

  41. Holdenrieder, S. et al. Soluble MICA in malignant diseases. Int. J. Cancer 118, 684–687 (2006).

    CAS  PubMed  Google Scholar 

  42. Oppenheim, D. E. et al. Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nature Immunol. 6, 928–937 (2005). An elegant study showing the immunosuppressive role of NKG2D ligands on NK-cell functions in mice.

    CAS  Google Scholar 

  43. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).

    CAS  PubMed  Google Scholar 

  45. Pardoll, D. M. Spinning molecular immunology into successful immunotherapy. Nature Rev. Immunol. 2, 227–238 (2002).

    CAS  Google Scholar 

  46. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  48. Takaoka, A. et al. Integration of interferon-α/β signalling to p53 responses in tumour suppression and antiviral defence. Nature 424, 516–523 (2003).

    CAS  PubMed  Google Scholar 

  49. Chaturvedi, V., Bodner, B., Qin, J. Z. & Nickoloff, B. J. Knock down of p53 levels in human keratinocytes increases susceptibility to type I and type II interferon-induced apoptosis mediated by a TRAIL dependent pathway. J. Dermatol. Sci. 41, 31–41 (2006).

    CAS  PubMed  Google Scholar 

  50. Stassi, G. et al. Thyroid cancer resistance to chemotherapeutic drugs via autocrine production of interleukin-4 and interleukin-10. Cancer Res. 63, 6784–6790 (2003).

    CAS  PubMed  Google Scholar 

  51. Wang, T. et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nature Med. 10, 48–54 (2004).

    PubMed  Google Scholar 

  52. Nabarro, S. et al. Coordinated oncogenic transformation and inhibition of host immune responses by the PAX3–FKHR fusion oncoprotein. J. Exp. Med. 202, 1399–1410 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kryczek, I. et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J. Exp. Med. 203, 871–881 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Pupa, S. M., Tagliabue, E., Menard, S. & Anichini, A. HER-2: a biomarker at the crossroads of breast cancer immunotherapy and molecular medicine. J. Cell. Physiol. 205, 10–18 (2005).

    CAS  PubMed  Google Scholar 

  55. Carbone, D. P. et al. Immunization with mutant p53- and K-ras-derived peptides in cancer patients: immune response and clinical outcome. J. Clin. Oncol. 23, 5099–5107 (2005).

    PubMed  Google Scholar 

  56. Muraoka-Cook, R. S., Dumont, N. & Arteaga, C. L. Dual role of transforming growth factor β in mammary tumorigenesis and metastatic progression. Clin. Cancer Res. 11, 937s–943s (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  58. Ghiringhelli, F. et al. Tumor cells convert immature myeloid dendritic cells into TGF-β-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J. Exp. Med. 202, 919–929 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    CAS  PubMed  Google Scholar 

  60. Zhang, Q. et al. Adoptive transfer of tumor-reactive transforming growth factor-β-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer. Cancer Res. 65, 1761–1769 (2005).

    CAS  PubMed  Google Scholar 

  61. Green, D. R. & Kroemer, G. The pathophysiology of mitochondrial cell death. Science 305, 626–629 (2004).

    CAS  PubMed  Google Scholar 

  62. Debatin, K. M. & Krammer, P. H. Death receptors in chemotherapy and cancer. Oncogene 23, 2950–2966 (2004).

    CAS  PubMed  Google Scholar 

  63. Kroemer, G. & Martin, S. J. Caspase-independent cell death. Nature Med. 11, 725–730 (2005).

    PubMed  Google Scholar 

  64. Ravi, R. et al. Resistance of cancers to immunologic cytotoxicity and adoptive immunotherapy via X-linked inhibitor of apoptosis protein expression and coexisting defects in mitochondrial death signaling. Cancer Res. 66, 1730–1739 (2006).

    CAS  PubMed  Google Scholar 

  65. Liu, K., Caldwell, S. A. & Abrams, S. I. Immune selection and emergence of aggressive tumor variants as negative consequences of Fas-mediated cytotoxicity and altered IFN-γ-regulated gene expression. Cancer Res. 65, 4376–4388 (2005).

    CAS  PubMed  Google Scholar 

  66. Andersen, M. H., Reker, S., Kvistborg, P., Becker, J. C. & thor Straten, P. Spontaneous immunity against Bcl-xL in cancer patients. J. Immunol. 175, 2709–2714 (2005).

    CAS  PubMed  Google Scholar 

  67. Ren, J. et al. MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90. Oncogene 25, 20–31 (2006).

    CAS  PubMed  Google Scholar 

  68. Monti, P. et al. Tumor-derived MUC1 mucins interact with differentiating monocytes and induce IL-10highIL-12low regulatory dendritic cell. J. Immunol. 172, 7341–7349 (2004).

    CAS  PubMed  Google Scholar 

  69. Carlos, C. A. et al. Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote TH1 type immunity. J. Immunol. 175, 1628–1635 (2005).

    CAS  PubMed  Google Scholar 

  70. Dohi, T., Beltrami, E., Wall, N. R., Plescia, J. & Altieri, D. C. Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis. J. Clin. Invest. 114, 1117–1127 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Andersen, M. H., Pedersen, L. O., Becker, J. C. & Straten, P. T. Identification of a cytotoxic T lymphocyte response to the apoptosis inhibitor protein survivin in cancer patients. Cancer Res. 61, 869–872 (2001).

    CAS  PubMed  Google Scholar 

  72. Asanuma, K., Tsuji, N., Endoh, T., Yagihashi, A. & Watanabe, N. Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells. J. Immunol. 172, 3922–3929 (2004).

    CAS  PubMed  Google Scholar 

  73. Igney, F. H. & Krammer, P. H. Tumor counterattack: fact or fiction? Cancer Immunol. Immunother. 54, 1127–1136 (2005).

    PubMed  Google Scholar 

  74. Wajant, H. CD95L/FasL and TRAIL in tumour surveillance and cancer therapy. Cancer Treat. Res. 130, 141–165 (2006).

    CAS  PubMed  Google Scholar 

  75. Bennett, M. W. et al. The Fas counterattack in vivo: apoptotic depletion of tumor-infiltrating lymphocytes associated with Fas ligand expression by human esophageal carcinoma. J. Immunol. 160, 5669–5675 (1998).

    CAS  PubMed  Google Scholar 

  76. Okada, K. et al. Frequency of apoptosis of tumor-infiltrating lymphocytes induced by Fas counterattack in human colorectal carcinoma and its correlation with prognosis. Clin. Cancer Res. 6, 3560–3564 (2000).

    CAS  PubMed  Google Scholar 

  77. Scott, C. L. et al. Apaf-1 and caspase-9 do not act as tumor suppressors in myc-induced lymphomagenesis or mouse embryo fibroblast transformation. J. Cell Biol. 164, 89–96 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Tanimoto, T. et al. Nuclear expression of cIAP-1, an apoptosis inhibiting protein, predicts lymph node metastasis and poor patient prognosis in head and neck squamous cell carcinomas. Cancer Lett. 224, 141–151 (2005).

    CAS  PubMed  Google Scholar 

  79. Tamm, I. et al. XIAP expression correlates with monocytic differentiation in adult de novo AML: impact on prognosis. Hematol. J. 5, 489–495 (2004).

    CAS  PubMed  Google Scholar 

  80. Soengas, M. S. et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409, 207–211 (2001).

    CAS  PubMed  Google Scholar 

  81. Umetani, N. et al. Allelic imbalance of APAF-1 locus at 12q23 is related to progression of colorectal carcinoma. Oncogene 23, 8292–8300 (2004).

    CAS  PubMed  Google Scholar 

  82. Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005). This article provides evidence that the immunogenicity of some chemotherapy protocols is influenced by the propensity of tumour cells to activate caspases.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Nikitina, E. Y. et al. Versatile prostate cancer treatment with inducible caspase and interleukin-12. Cancer Res. 65, 4309–4319 (2005).

    CAS  PubMed  Google Scholar 

  84. Amarnath, S. M. et al. In vitro quantification of the cytotoxic T lymphocyte response against human telomerase reverse transcriptase in breast cancer. Int. J. Oncol. 25, 211–217 (2004).

    CAS  PubMed  Google Scholar 

  85. Maecker, B. et al. Rare naturally occurring immune responses to three epitopes from the widely expressed tumour antigens hTERT and CYP1B1 in multiple myeloma patients. Clin. Exp. Immunol. 141, 558–562 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ichiki, Y. et al. Simultaneous cellular and humoral immune response against mutated p53 in a patient with lung cancer. J. Immunol. 172, 4844–4850 (2004).

    CAS  PubMed  Google Scholar 

  87. Della Porta, M. et al. Dendritic cells and vascular endothelial growth factor in colorectal cancer: correlations with clinicobiological findings. Oncology 68, 276–284 (2005).

    CAS  PubMed  Google Scholar 

  88. Ohm, J. E. et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101, 4878–4886 (2003).

    CAS  PubMed  Google Scholar 

  89. Yang, L. & Carbone, D. P. Tumor–host immune interactions and dendritic cell dysfunction. Adv. Cancer Res. 92, 13–27 (2004).

    CAS  PubMed  Google Scholar 

  90. Brown, J. R. & DuBois, R. N. COX-2: a molecular target for colorectal cancer prevention. J. Clin. Oncol. 23, 2840–2855 (2005).

    CAS  PubMed  Google Scholar 

  91. Stolina, M. et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J. Immunol. 164, 361–370 (2000).

    CAS  PubMed  Google Scholar 

  92. Lang, S. et al. Impaired monocyte function in cancer patients: restoration with a cyclooxygenase-2 inhibitor. FASEB J. 17, 286–288 (2003).

    CAS  PubMed  Google Scholar 

  93. Boles, K. S., Barchet, W., Diacovo, T., Cella, M. & Colonna, M. The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM. Blood 106, 779–786 (2005).

    CAS  PubMed  Google Scholar 

  94. Kroemer, G. & Jaattela, M. Lysosomes and autophagy in cell death control. Nature Rev. Cancer 5, 886–897 (2005).

    CAS  Google Scholar 

  95. Calderwood, S. K., Theriault, J. R. & Gong, J. Message in a bottle: role of the 70-kDa heat shock protein family in anti-tumor immunity. Eur. J. Immunol. 35, 2518–2527 (2005).

    CAS  PubMed  Google Scholar 

  96. Binder, R. J. & Srivastava, P. K. Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells. Nature Immunol. 6, 593–599 (2005).

    CAS  Google Scholar 

  97. Gastpar, R. et al. Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. Cancer Res. 65, 5238–5247 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Stefanidakis, M. & Koivunen, E. Cell-surface association between matrix metalloproteinases: role of the complexes in leukocyte migration and cancer progression. Blood 108, 1441–1450 (2006).

    CAS  PubMed  Google Scholar 

  99. So, T. et al. Haplotype loss of HLA class I antigen as an escape mechanism from immune attack in lung cancer. Cancer Res. 65, 5945–5952 (2005).

    CAS  PubMed  Google Scholar 

  100. Atkins, D. et al. MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma. Int. J. Cancer 109, 265–273 (2004).

    CAS  PubMed  Google Scholar 

  101. Medema, J. P. et al. Blockade of the granzyme B/perforin pathway through overexpression of the serine protease inhibitor PI-9/SPI-6 constitutes a mechanism for immune escape by tumors. Proc. Natl Acad. Sci. USA 98, 11515–11520 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Ochsenbein, A. F. Immunological ignorance of solid tumors. Springer Semin. Immunopathol. 27, 19–35 (2005).

    PubMed  Google Scholar 

  103. Bronte, V. & Zanovello, P. Regulation of immune responses by L-arginine metabolism. Nature Rev. Immunol. 5, 641–654 (2005). A stimulating review about the characterization of myeloid suppressor cells.

    CAS  Google Scholar 

  104. Uyttenhove, C. et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Med. 9, 1269–1274 (2003).

    CAS  PubMed  Google Scholar 

  105. Terness, P. et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J. Exp. Med. 196, 447–457 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Huang, Y., Obholzer, N., Fayad, R. & Qiao, L. Turning on/off tumor-specific CTL response during progressive tumor growth. J. Immunol. 175, 3110–3116 (2005).

    CAS  PubMed  Google Scholar 

  107. Zhou, G., Lu, Z., McCadden, J. D., Levitsky, H. I. & Marson, A. L. Reciprocal changes in tumor antigenicity and antigen-specific T cell function during tumor progression. J. Exp. Med. 200, 1581–1592 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Sakaguchi, S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol. 22, 531–562 (2004).

    CAS  PubMed  Google Scholar 

  109. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Rev. Cancer 5, 263–274 (2005).

    CAS  Google Scholar 

  110. Terabe, M. & Berzofsky, J. A. Immunoregulatory T cells in tumor immunity. Curr. Opin. Immunol. 16, 157–162 (2004). An overview of the suppressive role of IL-13 produced by NKT cells during tolerance induced by irradiation with ultraviolet light. This suppressive process involves myeloid suppressor cells and TGFβ.

    CAS  PubMed  Google Scholar 

  111. Guiducci, C., Vicari, A. P., Sangaletti, S., Trinchieri, G. & Colombo, M. P. Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Res. 65, 3437–3446 (2005).

    CAS  PubMed  Google Scholar 

  112. Wei, S. et al. Plasmacytoid dendritic cells induce CD8+ regulatory T cells in human ovarian carcinoma. Cancer Res. 65, 5020–5026 (2005).

    CAS  PubMed  Google Scholar 

  113. Coudert, J. D. et al. Altered NKG2D function in NK cells induced by chronic exposure to NKG2D ligand-expressing tumor cells. Blood 106, 1711–1717 (2005).

    CAS  PubMed  Google Scholar 

  114. Coleman, S. et al. Recovery of CD8+ T-cell function during systemic chemotherapy in advanced ovarian cancer. Cancer Res. 65, 7000–7006 (2005).

    CAS  PubMed  Google Scholar 

  115. Daniel, D. et al. Immune enhancement of skin carcinogenesis by CD4+ T cells. J. Exp. Med. 197, 1017–1028 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Faber, P. et al. Frequent genomic alterations in epithelium measured by microsatellite instability following allogeneic hematopoietic cell transplantation in humans. Blood 107, 3389–3396 (2005).

    PubMed  Google Scholar 

  117. Conticello, C. et al. IL-4 protects tumor cells from anti-CD95 and chemotherapeutic agents via up-regulation of antiapoptotic proteins. J. Immunol. 172, 5467–5477 (2004).

    CAS  PubMed  Google Scholar 

  118. Oppenheim, J. J. et al. Autoantigens act as tissue-specific chemoattractants. J. Leukoc. Biol. 77, 854–861 (2005).

    CAS  PubMed  Google Scholar 

  119. Bonnotte, B., Crittenden, M., Larmonier, N., Gough, M. & Vile, R. G. MIP-3α transfection into a rodent tumor cell line increases intratumoral dendritic cell infiltration but enhances (facilitates) tumor growth and decreases immunogenicity. J. Immunol. 173, 4929–4935 (2004).

    CAS  PubMed  Google Scholar 

  120. Curiel, T. J. et al. Dendritic cell subsets differentially regulate angiogenesis in human ovarian cancer. Cancer Res. 64, 5535–5538 (2004).

    CAS  PubMed  Google Scholar 

  121. Coukos, G., Benencia, F., Buckanovich, R. J. & Conejo-Garcia, J. R. The role of dendritic cell precursors in tumour vasculogenesis. Br. J. Cancer 92, 1182–1187 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Berd, D. & Mastrangelo, M. J. Effect of low dose cyclophosphamide on the immune system of cancer patients: reduction of T-suppressor function without depletion of the CD8+ subset. Cancer Res. 47, 3317–3321 (1987).

    CAS  PubMed  Google Scholar 

  123. Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. (in the press).

  124. Borg, C. et al. Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects. J. Clin. Invest. 114, 379–388 (2004). The first study to show the side-effect of imatinib mesylate on the immune system of mice and patients.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Fulda, S. & Debatin, K. M. Targeting apoptosis pathways in cancer therapy. Curr. Cancer Drug Targets 4, 569–576 (2004).

    CAS  PubMed  Google Scholar 

  126. Reits, E. A. et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J. Exp. Med. 203, 1259–1271 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Armeanu, S. et al. Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate. Cancer Res. 65, 6321–6329 (2005).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported by grants from the European Union, the Ligue Nationale contre le Cancer (France), Cancéropôle Île-de-France (France) and the Institut National du Cancer (France).

Author information

Authors and Affiliations

  1. U805 Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine Paris-Sud-Université Paris XI, Institut Gustave-Roussy, 39 rue Camille-Desmoulins, Villejuif, F-94805, France

    Laurence Zitvogel

  2. Centre National de la Recherche Scientifique FRE29239, Institut Gustave-Roussy, 39 rue Camille-Desmoulins, Villejuif, F-94805, France

    Antoine Tesniere & Guido Kroemer

Authors
  1. Laurence Zitvogel
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Antoine Tesniere
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Guido Kroemer
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Guido Kroemer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Institut Gustave-Roussy

Glossary

Angiogenesis

The development of new blood vessels from existing blood vessels. It is frequently associated with tumour development and inflammation.

Natural killer T cells

(NKT cells). A heterogeneous subset of T cells that are characterized by the co-expression of semi-invariant T-cell receptor α-chains together with NK-cell markers.

Perforin

A component of cytolytic granules that participates in the permeabilization of plasma membranes, allowing granzymes and other cytotoxic components to enter target cells.

NKG2D

(Natural-killer group 2, member D). A lectin-type activating receptor that is encoded by the NK complex and is expressed at the surface of NK cells, NKT cells, γδ T cells and some cytolytic CD8+ αβ T cells. The ligands for NKG2D are MHC-class-I-polypeptide-related sequence A (MICA) and MICB in humans, and retinoic acid early transcript 1 (RAE1) and H60 in mice. Such ligands are generally expressed at the surface of infected, stressed or transformed cells.

IFN-producing killer DC

(IKDC). A dendritic cell (DC) that expresses markers of both natural killer cells and B cells but lacks markers of plasmacytoid DCs and T cells, as well as co-stimulatory molecules. These DCs have been isolated only in mouse models. They respond to a large variety of tumour cells by producing interferon-γ (IFNγ), and they kill these tumour cells in the absence of exogenous stimulation.

Pre-malignant

An intermediate step before full transformation into a tumour cell has occurred.

Monoclonal gammopathy

A tumour (most of which develop into multiple myelomas) that is derived from B cells and produces one type of monoclonal antibody, which can be detected in the serum.

Tumour-suppressor protein

A protein encoded by a gene that, when eliminated or inactivated, allows the development of cancer. These proteins often determine cell-cycle checkpoints or facilitate the induction of apoptosis.

p53

An important transcription factor that is activated by many genotoxic insults and induces cellular senescence or apoptosis. The gene that encodes p53 is frequently mutated or functionally inactivated in cancer cells.

T helper 1 cell

(TH1 cell). There are two main subsets of activated CD4+ T cells: TH1 cells and TH2 cells. TH1 cells produce interferon-γ and tumour-necrosis factor, thereby promoting cell-mediated immunity. TH2 cells produce interleukin-4 (IL-4), IL-5 and IL-13, thereby supporting humoral immunity and counteracting TH1-cell responses.

CD4+CD25+ regulatory T cell

(TReg cell). A T cell that expresses CD4, CD25 (also known as the interleukin-2 receptor α-chain) and the transcription factor T-bet, and is activated in an antigen-specific, MHC-class-II-restricted manner, but inhibits T cells and natural killer cells in a nonspecific manner, in part by producing transforming growth factor-β.

Chediak–Higashi syndrome

A rare autosomal recessive genetic disorder that is caused by mutations in the gene CHS1 (Chediak–Higashi syndrome 1; also known as LYST), which is involved in lysosome fission and secretion.

Oncogene

A gene that when overexpressed or when incorporating a gain-of-function mutation contributes to oncogenesis.

DNA-damage response

The cellular response that is usually elicited by agents that damage DNA, such as ionizing radiation or mutagenic chemicals. The response involves the activation of DNA-damage foci, which have phosphorylated histone H2AX (histone 2A family, member X) as a hallmark, and it elicits cell-cycle arrest, DNA repair or apoptosis.

Senescence

An almost irreversible stage of permanent arrest in the gap 0/1 (G0/1) stage of the cell cycle. Such arrest is associated with morphological changes (flattening of the cells), metabolic changes, and gene-expression changes (including induction of expression of the senescence-associated protein β-galactosidase), the induction of which depends on the tumour-suppressor protein p53 and cell-cycle blockers such as WAF1 (wild-type p53-activated fragment 1; also known as p21) and INK4A (also known as p16).

Mitochondrial outer-membrane permeabilization

(MOMP). An apoptosis-associated process that results in the release of apoptosis-inducing proteins — such as cytochrome c, apoptosis-inducing factor, and second mitochondria-derived activator of caspase (also known as DIABLO) — from the mitochondrial intermembrane space into the cytosol.

Death receptors

A family of cell-surface receptors that can mediate cell death following ligand-induced trimerization. The best-studied members include tumour-necrosis-factor (TNF) receptor 1, CD95 (also known as FAS) and two receptors for TNF-related apoptosis-inducing ligand (TRAILR1 and TRAILR2).

Caspases

A family of cysteine proteases that cleave proteins carboxy-terminal to asparagine residues. Initiator caspases are typically activated in response to particular stimuli: for example, caspase-8 is activated after death-receptor ligation; caspase-9, after apoptosome activation; caspase-2, after DNA damage. By contrast, effector caspases (that is, caspase-3, caspase-6 and caspase-7) are particularly important for the ordered dismantling of vital cellular structures.

B-cell-lymphoma-2 family

(BCL-2 family). A family of proteins that contain at least one BCL-2-homology domain (BH). The family is classified into three groups: anti-apoptotic multidomain proteins, such as BCL-2, BCL-XL and MCL1 (myeloid-cell leukaemia sequence 1), which contain four BHs; pro-apoptotic multidomain proteins, such as BAX (BCL-2-associated X protein) and BAK (BCL-2 antagonist/killer), which contain three BHs; and a pro-apoptotic subfamily of proteins that contain only one BH, the BH3-only proteins.

Apoptosome

A complex that forms when cytochrome c is released from mitochondria and interacts with the cytosolic protein apoptotic-protease-activating factor 1 (APAF1), which in turn recruits pro-caspase-9. In the presence of ATP, this interaction results in the allosteric activation of caspase-9 and the formation of a caspase-3-activation complex.

Cathepsins

A class of cysteine proteases that are localized mainly in lysosomes and lysosome-like organelles.

Damage-associated molecular pattern molecules

(DAMPs). As a result of cellular stress, cellular damage and non-physiological cell death, DAMPs are released from the degraded stroma (for example, hyaluronate), from the nucleus (for example, high-mobility group box 1 protein, HMGB1) and from the cytosol (for example, ATP, uric acid, S100 calcium-binding proteins and heat-shock proteins). Such DAMPs are thought to elicit local inflammatory reactions.

Cross-priming

The initiation of a CD8+ T-cell response to an antigen that is not present within antigen-presenting cells (APCs). This occurs through the ability of certain APCs to present peptides that are derived from exogenous antigens in the context of MHC class I molecules. This property is atypical, because the peptides that are presented in the context of MHC class I molecules by most cells are derived from endogenous proteins.

Exosomes

Small lipid-bilayer vesicles that are released from dendritic cells (DCs) and tumour cells. Characteristically, exosomes are enriched in MHC complexes, tetraspanins, and heat-shock protein 70 (HSP70) and HSP90, all of which could be cross-presented by DCs to activate T cells.

Plasmacytoid DC

An immature dendritic cell (DC) with a morphology that resembles that of a plasmablast. Plasmacytoid DCs produce large amounts of type I interferons in response to viral infection.

Microsatellite instability

A term that refers to tumours in which genetic instability occurs as a result of a high mutation rate, mainly in short nucleotide repeats (which are known as microsatellites). Cancers with microsatellite instability are associated with defects in DNA mismatch-repair genes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol 6, 715–727 (2006). https://doi.org/10.1038/nri1936

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1936

This article is cited by

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