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.

Paradoxical roles of the immune system during cancer development

Key Points

  • Adaptive and innate immune cells regulate tissue homeostasis and efficient wound healing.

  • Altered interactions between adaptive and innate immune cells can lead to chronic inflammatory disorders.

  • In cancers, an abundance of infiltrating innate immune cells, such as macrophages, mast cells and neutrophils, correlates with increased angiogenesis and/or poor prognosis.

  • In cancers, an abundance of infiltrating lymphocytes correlates with favourable prognosis.

  • Chronic inflammatory conditions enhance a predisposition to cancer development.

  • Long-term usage of non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors reduces cancer incidence.

  • Polymorphisms in genes that regulate immune balance influence cancer risk.

  • Immune status in humans and in mouse models affects the risk of cancer development in an aetiology-dependent manner.

  • Genetic elimination or depletion of immune cells alters cancer progression in experimental models.

  • Activation of antitumour adaptive immune responses can suppress tumour growth.

Abstract

The main function of the mammalian immune system is to monitor tissue homeostasis, to protect against invading or infectious pathogens and to eliminate damaged cells. Therefore, it is surprising that cancer occurs with such a high frequency in humans. Recent insights that have been gained from clinical studies and experimental mouse models of carcinogenesis expand our understanding of the complex relationship between immune cells and developing tumours. Here, we examine the paradoxical role of adaptive and innate leukocytes as crucial regulators of cancer development and highlight recent insights that have been gained by manipulating immune responses in mouse models of de novo and spontaneous tumorigenesis.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Inflammation in human breast and prostate cancer.
Figure 2: Inflammation and angiogenesis are hallmarks of squamous carcinogenesis in HPV16 transgenic mice.
Figure 3: Humoral immune response in breast and prostate cancer.
Figure 4: A model of innate and adaptive immune-cell function during inflammation-associated cancer development.

References

  1. Hamerman, J. A., Ogasawara, K. & Lanier, L. L. NK cells in innate immunity. Curr. Opin. Immunol. 17, 29–35 (2005).

    CAS  PubMed  Google Scholar 

  2. Degli-Esposti, M. A. & Smyth, M. J. Close encounters of different kinds: dendritic cells and NK cells take centre stage. Nature Rev. Immunol. 5, 112–124 (2005).

    CAS  Google Scholar 

  3. Raulet, D. H. Interplay of natural killer cells and their receptors with the adaptive immune response. Nature Immunol. 5, 996–1002 (2004). References 1–3 are comprehensive reviews on the role of dendritic and natural killer cells during tumour development.

    CAS  Google Scholar 

  4. Finch, C. E. & Crimmins, E. M. Inflammatory exposure and historical changes in human life-spans. Science 305, 1736–1739 (2004). A thoughtful analysis of historical changes in human exposure to inflammatory agents that are correlated with cancer incidence and lifespan.

    CAS  PubMed  Google Scholar 

  5. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

    CAS  PubMed  Google Scholar 

  6. Coca, S. et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer 79, 2320–2328 (1997).

    CAS  PubMed  Google Scholar 

  7. Ishigami, S. et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer 88, 577–583 (2000).

    CAS  PubMed  Google Scholar 

  8. Ribatti, D. et al. Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur. J. Clin. Invest. 33, 420–425 (2003).

    CAS  PubMed  Google Scholar 

  9. Imada, A., Shijubo, N., Kojima, H. & Abe, S. Mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma. Eur. Respir. J. 15, 1087–1093 (2000).

    CAS  PubMed  Google Scholar 

  10. Leek, R. D. et al. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 56, 4625–4629 (1996).

    CAS  PubMed  Google Scholar 

  11. Leek, R. D., Landers, R. J., Harris, A. L. & Lewis, C. E. Necrosis correlates with high vascular density and focal macrophage infiltration in invasive carcinoma of the breast. Br. J. Cancer 79, 991–995 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Balkwill, F., Charles, K. A. & Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211–217 (2005). A timely and detailed review of clinical and experimental literature that discusses paracrine communication networks between immune cells and cells at risk for cancer development.

    CAS  PubMed  Google Scholar 

  13. Pagano, J. S. et al. Infectious agents and cancer: criteria for a causal relation. Semin. Cancer Biol. 14, 453–471 (2004).

    CAS  PubMed  Google Scholar 

  14. Velicer, C. M. et al. Antibiotic use in relation to the risk of breast cancer. JAMA 291, 827–835 (2004).

    CAS  PubMed  Google Scholar 

  15. Enzler, T. et al. Deficiencies of GM-CSF and interferon γ link inflammation and cancer. J. Exp. Med. 197, 1213–1219 (2003). A detailed analysis of immune-competent mice that are deficient for GMCSF and IFNγ, which demonstrates that failure to normalize tissue homeostasis and clear low-level microbial infections results in chronic inflammation that underlies an increased incidence of haematologic and solid-tissue cancers.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Korzenik, J. R., Dieckgraefe, B. K., Valentine, J. F., Hausman, D. F. & Gilbert, M. J. Sargramostim for active Crohn's disease. N. Engl. J. Med. 352, 2193–2201 (2005).

    CAS  PubMed  Google Scholar 

  17. Dannenberg, A. & Subbaramaiah . Targeting cyclooxygenase-2 in human neoplasia: rationale and promise. Cancer Cell 4, 431–436 (2003).

    CAS  PubMed  Google Scholar 

  18. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nature Rev. Cancer 5, 263–274 (2005). An excellent review that provides an extensive overview of immunosuppressive networks in the microenvironment of developing tumours.

    CAS  Google Scholar 

  19. Finke, J., Ferrone, S., Frey, A., Mufson, A. & Ochoa, A. Where have all the T cells gone? Mechanisms of immune evasion by tumors. Immunol. Today 20, 158–160 (1999).

    CAS  PubMed  Google Scholar 

  20. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nature Med. 10, 942–94 (2004).

    CAS  PubMed  Google Scholar 

  21. Serafini, P. et al. Derangement of immune responses by myeloid suppressor cells. Cancer Immunol. Immunother. 53, 64–72 (2004).

    CAS  PubMed  Google Scholar 

  22. Coussens, L. M., Hanahan, D. & Arbeit, J. M. Genetic predisposition and parameters of malignant progression in K14-HPV16 transgenic mice. Am. J. Pathol. 149, 1899–1917 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Arbeit, J., Howley, P. & Hanahan, D. Chronic estrogen-induced cervical and vaginal squamous carcinogenesis in HPV16 transgenic mice. Proc. Natl Acad. Sci. USA 93, 2930–2935 (1996).

    CAS  PubMed  Google Scholar 

  24. Smith-McCune, K., Zhu, Y. H., Hanahan, D. & Arbeit, J. Cross-species comparison of angiogenesis during the premalignant stages of squamous carcinogenesis in the human cervix and K14-HPV16 transgenic mice. Cancer Res. 57, 1294–1300 (1997).

    CAS  PubMed  Google Scholar 

  25. van Kempen, L. C. L. et al. Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment. Differentiation 70, 610–623 (2002).

    PubMed  Google Scholar 

  26. Giraudo, E., Inoue, M. & Hanahan, D. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical carcinogenesis. J. Clin. Invest. 114, 623–633 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Coussens, L. M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005). A study from the authors' laboratory that reports that inflammation-associated cancer development in skin-cancer-prone transgenic mice is dependent upon serum factors that are derived from activated peripheral B lymphocytes, so revealing the complexity of interactions between innate and adaptive immune cells that regulate epithelial cancer development.

    CAS  PubMed  Google Scholar 

  29. Lin, E. Y., Nguyen, A. V., Russell, R. G. & Pollard, J. W. Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J. Exp. Med. 193, 727–740 (2001). Using the well-characterized MMTV-PyMT model of mammary carcinogenesis, the authors rendered mice CSF1-deficient to block macrophage recruitment into neoplastic tissue and therefore demonstrated that macrophages deliver permissive factors necessary for development of late-stage carcinomas and pulmonary metastases.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nature Rev. Cancer 4, 71–78 (2004). A detailed review on the role of macrophages during mammary carcinogenesis.

    CAS  Google Scholar 

  31. Sparmann, A. & Bar-Sagi, D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 6, 447–458 (2004).

    CAS  PubMed  Google Scholar 

  32. Smyth, M. J., Crowe, N. Y. & Godfrey, D. I. NK cells and NKT cells collaborate in host protection from methylcholanthrene-induced fibrosarcoma. Int. Immunol. 13, 459–463 (2001).

    CAS  PubMed  Google Scholar 

  33. Hayakawa, Y. et al. IFN-γ-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, α-galactosylceramide. Blood 100, 1728–1733 (2002).

    CAS  PubMed  Google Scholar 

  34. Esposito, I. et al. Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J. Clin. Pathol. 57, 630–636 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Yano, H. et al. Mast cell infiltration around gastric cancer cells correlates with tumor angiogenesis and metastasis. Gastric Cancer 2, 26–32 (1999).

    PubMed  Google Scholar 

  36. Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in cancer progression. Nature Rev. Cancer 2, 161–174 (2002).

    CAS  Google Scholar 

  37. Coussens, L. M., Tinkle, C. L., Hanahan, D. & Werb, Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481–490 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Huang, S. et al. Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in mice. J. Natl Cancer Inst. 94, 1134–1142 (2002).

    CAS  PubMed  Google Scholar 

  39. Hiratsuka, S. et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell 2, 289–300 (2002).

    CAS  Google Scholar 

  40. Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nature Cell Biol. 2, 737–744 (2000).

    CAS  PubMed  Google Scholar 

  41. Overall, C. M., McQuibban, G. A. & Clark-Lewis, I. Discovery of chemokine substrates for matrix metalloproteinases by exosite scanning: a new tool for degradomics. Biol. Chem. 383, 1059–1066 (2002).

    CAS  PubMed  Google Scholar 

  42. Lynch, C. C. et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell 7, 485–496 (2005). A provocative study that reveals a previously unknown role for MMP7/matrilysin as a crucial regulator of osteolysis during prostate-cancer bone metastases by virtue of its ability to regulate bioavailability of RANKL.

    CAS  PubMed  Google Scholar 

  43. Coleman, R. E. Bisphosphonates in breast cancer. Ann. Oncol. 16, 687–695 (2005).

    CAS  PubMed  Google Scholar 

  44. Psaty, B. M. & Furberg, C. D. COX-2 inhibitors — lessons in drug safety. N. Engl. J. Med. 352, 1133–1135 (2005).

    CAS  PubMed  Google Scholar 

  45. Liu, C. H. et al. Overexpression of cyclooxygenase-2 is sufficient to induce tumorigenesis in transgenic mice. J. Biol. Chem. 276, 18563–18569 (2001).

    CAS  PubMed  Google Scholar 

  46. Jacoby, R. F., Seibert, K., Cole, C. E., Kelloff, G. & Lubet, R. A. The cyclooxygenase-2 inhibitor celecoxib is a potent preventive and therapeutic agent in the min mouse model of adenomatous polyposis. Cancer Res. 60, 5040–5044 (2000).

    CAS  PubMed  Google Scholar 

  47. Oshima, M. et al. Suppression of intestinal polyposis in ApcΔ716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87, 803–809 (1996).

    CAS  PubMed  Google Scholar 

  48. Zha, S., Yegnasubramanian, V., Nelson, W. G., Isaacs, W. B. & De Marzo, A. M. Cyclooxygenases in cancer: progress and perspective. Cancer Lett. 215, 1–20 (2004).

    CAS  PubMed  Google Scholar 

  49. Basu, G. D. et al. Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer. Mol. Cancer Res. 2, 632–642 (2004).

    CAS  PubMed  Google Scholar 

  50. Chang, S. H., Ai, Y., Breyer, R. M., Lane, T. F. & Hla, T. The prostaglandin E2 receptor EP2 is required for cyclooxygenase 2-mediated mammary hyperplasia. Cancer Res. 65, 4496–4499 (2005).

    CAS  PubMed  Google Scholar 

  51. Barbera-Guillem, E., Nyhus, J. K., Wolford, C. C., Friece, C. R. & Sampsel, J. W. Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. Cancer Res. 62, 7042–7049 (2002).

    CAS  PubMed  Google Scholar 

  52. Szlosarek, P. W. & Balkwill, F. R. Tumour necrosis factor α: a potential target for the therapy of solid tumours. Lancet Oncol. 4, 565–573 (2003).

    CAS  PubMed  Google Scholar 

  53. Madhusudan, S. et al. A phase II study of etanercept (Enbrel), a tumor necrosis factor α inhibitor in patients with metastatic breast cancer. Clin. Cancer Res. 10, 6528–6534 (2004).

    CAS  PubMed  Google Scholar 

  54. Pikarsky, E. et al. NF-κB functions as a tumour promoter in inflammation-associated cancer. Nature 431, 461–466 (2004).

    CAS  PubMed  Google Scholar 

  55. Greten, F. R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004). These two elegant studies use state-of-the-art conditional-knockout mice in combination with different chemical carcinogenesis strategies to cause inflammation-induced hepatocellular carcinoma or colitis-associated cancer, thereby demonstrating that inactivation of NFκB signalling in cells at risk for malignant conversion or in infiltrating inflammatory cells results in attenuated cancer formation. This highlights the necessity of paracrine interactions for cancer development.

    CAS  PubMed  Google Scholar 

  56. Gabrilovich, D. I., Velders, M. P., Sotomayor, E. M. & Kast, W. M. Mechanism of immune dysfunction in cancer mediated by immature Gr1+ myeloid cells. J. Immunol. 166, 5398–5406 (2001).

    CAS  PubMed  Google Scholar 

  57. Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163, 5211–5218 (1999).

    CAS  Google Scholar 

  58. Onizuka, S. et al. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor α) monoclonal antibody. Cancer Res. 59, 3128–3133 (1999).

    CAS  PubMed  Google Scholar 

  59. Seitz, C. S., Lin, Q., Deng, H. & Khavari, P. A. Alterations in NF-κB function in transgenic epithelial tissue demonstrate a growth inhibitory role for NF-κB. Proc. Natl Acad. Sci. USA 95, 2307–2312 (1998).

    CAS  PubMed  Google Scholar 

  60. Dajee, M. et al. NF-κB blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639–643 (2003).

    CAS  PubMed  Google Scholar 

  61. Scott, K. A. et al. An anti-tumor necrosis factor-a antibody inhibits the development of experimental skin tumors. Mol. Cancer Ther. 2, 445–451 (2003).

    CAS  PubMed  Google Scholar 

  62. Wang, C. Y., Cusack, J. C. Jr, Liu, R. & Baldwin, A. S. Jr . Control of inducible chemoresistance: enhanced anti-tumor therapy through increased apoptosis by inhibition of NF-κB. Nature Med. 5, 412–417 (1999).

    PubMed  Google Scholar 

  63. Lenz, H. J. Clinical update: proteasome inhibitors in solid tumors. Cancer Treat. Rev. 29, 41–48 (2003).

    CAS  PubMed  Google Scholar 

  64. Boshoff, C. & Weiss, R. AIDS-related malignancies. Nature Rev. Cancer 2, 373–382 (2002).

    CAS  Google Scholar 

  65. Clifford, G. M. et al. Cancer risk in the Swiss HIV Cohort Study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. J. Natl Cancer Inst. 97, 425–432 (2005).

    PubMed  Google Scholar 

  66. Herrero, J. I. et al. De novo neoplasia after liver transplantation: an analysis of risk factors and influence on survival. Liver Transpl. 11, 89–97 (2005).

    PubMed  Google Scholar 

  67. Fung, J. J. et al. De novo malignancies after liver transplantation: a major cause of late death. Liver Transpl. 7, S109–S118 (2001).

    CAS  PubMed  Google Scholar 

  68. Rosenberg, S. A., Yang, J. C. & Restifo, N. P. Cancer immunotherapy: moving beyond current vaccines. Nature Med. 10, 909–915 (2004). A thoughtful assessment of current anticancer immunotherapeutical approaches and critical analysis of successes and failures with current strategies.

    CAS  PubMed  Google Scholar 

  69. de Visser, K. E., Schumacher, T. N. & Kruisbeek, A. M. CD8+ T cell tolerance and cancer immunotherapy. J. Immunother. 26, 1–11 (2003).

    CAS  PubMed  Google Scholar 

  70. Overwijk, W. W. Breaking tolerance in cancer immunotherapy: time to ACT. Curr. Opin. Immunol. 17, 187–194 (2005).

    CAS  PubMed  Google Scholar 

  71. 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 

  72. Daniel, D. et al. CD4+ T Cell-mediated antigen-specific immunotherapy in a mouse model of cervical cancer. Cancer Res. 65, 2018–2025 (2005).

    CAS  PubMed  Google Scholar 

  73. Girardi, M. et al. Regulation of cutaneous malignancy by γδ T cells. Science 294, 605–609 (2001). This study highlights a dual role for adaptive immunity during chemically induced skin carcinogenesis and reveals that the absence of γδ T cells results in increased susceptibility to MCA- and DMBA/TPA-induced carcinomas, whereas the absence of αβ T cells only increases suceptibility to MCA-induced carcinomas, and reduces susceptibility to DMBA/TPA-induced carcinomas.

    CAS  PubMed  Google Scholar 

  74. Smyth, M. J. & Godfrey, D. I. NKT cells and tumor immunity — a double-edged sword. Nature Immunol. 1, 459–460 (2000).

    CAS  Google Scholar 

  75. Papamichail, M., Perez, S. A., Gritzapis, A. D. & Baxevanis, C. N. Natural killer lymphocytes: biology, development, and function. Cancer Immunol. Immunother. 53, 176–186 (2004).

    PubMed  Google Scholar 

  76. Terabe, M. et al. NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nature Immunol. 1, 515–520 (2000).

    CAS  Google Scholar 

  77. Moodycliffe, A. M., Nghiem, D., Clydesdale, G. & Ullrich, S. E. Immune suppression and skin cancer development: regulation by NKT cells. Nature Immunol. 1, 521–525 (2000).

    CAS  Google Scholar 

  78. Hoebe, K., Janssen, E. & Beutler, B. The interface between innate and adaptive immunity. Nature Immunol. 5, 971–974 (2004). An excellent review of the complexities of interactions that regulate efficient and appropriate adaptive and innate immune-cell interactions.

    CAS  Google Scholar 

  79. Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).

    CAS  PubMed  Google Scholar 

  80. Gorman, C., Leandro, M. & Isenberg, D. B cell depletion in autoimmune disease. Arthritis Res. Ther. 5, 17–21 (2003).

    Google Scholar 

  81. Randolph, G. J., Angeli, V. & Swartz, M. A. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nature Rev. Immunol. 5, 617–628 (2005).

    CAS  Google Scholar 

  82. Snell, G. D. Incompatibility reactions to tumor homotransplants with particular reference to the role of the tumor: a review. Cancer Res. 17, 2–10 (1957).

    CAS  PubMed  Google Scholar 

  83. Kaliss, N. Immunological enhancement of tumor homografts in mice: a review. Cancer Res. 18, 992–1003 (1958).

    CAS  PubMed  Google Scholar 

  84. Ran, M. & Witz, I. P. Tumor-associated immunoglobulins. Enhancement of syngeneic tumors by IgG2-containing tumor eluates. Int. J. Cancer 9, 242–247 (1972).

    CAS  PubMed  Google Scholar 

  85. Agassy-Cahalon, L., Yaakubowicz, M., Witz, I. P. & Smorodinsky, N. I. The immune system during the precancer period: naturally-occurring tumor reactive monoclonal antibodies and urethane carcinogenesis. Immunol. Lett. 18, 181–189 (1988).

    CAS  PubMed  Google Scholar 

  86. Brodt, P. & Gordon, J. Natural resistance mechanisms may play a role in protection against chemical carcinogenesis. Cancer Immunol. Immunother. 13, 125–127 (1982).

    CAS  PubMed  Google Scholar 

  87. Monach, P. A., Schreiber, H. & Rowley, D. A. CD4+ and B lymphocytes in transplantation immunity. II. Augmented rejection of tumor allografts by mice lacking B cells. Transplantation 55, 1356–1361 (1993).

    CAS  PubMed  Google Scholar 

  88. Ibanez, O. M. et al. Low antibody responsiveness is found to be associated with resistance to chemical skin tumorigenesis in several lines of Biozzi mice. Cancer Lett. 136, 153–158 (1999).

    CAS  PubMed  Google Scholar 

  89. Siegel, C. T. et al. Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein. J. Exp. Med. 191, 1945–1956 (2000). Using classical immunological approaches, this is a clear study reporting that active immunization can result in enhancement of chemically induced tumors, which correlates with induction of humoral immune responses in experimental mouse models. This indicates that immunotherapeutical approaches must consider the duality of immunomodulation therapies.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Barbera-Guillem, E., May, K. F. Jr, Nyhus, J. K. & Nelson, M. B. Promotion of tumor invasion by cooperation of granulocytes and macrophages activated by anti-tumor antibodies. Neoplasia 1, 453–460 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Tomer, Y., Sherer, Y. & Shoenfeld, Y. Autoantibodies, autoimmunity and cancer. Oncol. Rep. 5, 753–761 (1998).

    CAS  PubMed  Google Scholar 

  92. Tan, E. M. & Shi, F. D. Relative paradigms between autoantibodies in lupus and autoantibodies in cancer. Clin. Exp. Immunol. 134, 169–177 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Edwards, J. C. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).

    CAS  PubMed  Google Scholar 

  94. Oligino, T. J. & Dalrymple, S. A. Targeting B cells for the treatment of rheumatoid arthritis. Arthritis Res. Ther. 5, 7–11 (2003).

    Google Scholar 

  95. Coussens, L. M., Fingleton, B. & Matrisian, L. M. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295, 2387–2392 (2002).

    CAS  PubMed  Google Scholar 

  96. Whitcomb, D. C. Inflammation and cancer V. Chronic pancreatitis and pancreatic cancer. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G315–G319 (2004).

    CAS  PubMed  Google Scholar 

  97. De Luca, A. & Iaquinto, G. Helicobacter pylori and gastric diseases: a dangerous association. Cancer Lett. 213, 1–10 (2004).

    CAS  PubMed  Google Scholar 

  98. Brechot, C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. Gastroenterology 127, 56–61 (2004).

    Google Scholar 

  99. Parsonnet, J. Molecular mechanisms for inflammation-promoted pathogenesis of cancer — The Sixteenth International Symposium of the Sapporo Cancer Seminar. Cancer Res. 57, 3620–3624 (1997).

    CAS  PubMed  Google Scholar 

  100. Schmielau, J. & Finn, O. J. Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of T-cell function in advanced cancer patients. Cancer Res. 61, 4756–4760 (2001).

    CAS  PubMed  Google Scholar 

  101. Stuart, L. M. & Ezekowitz, R. A. Phagocytosis: elegant complexity. Immunity 22, 539–550 (2005).

    CAS  PubMed  Google Scholar 

  102. Gallagher, B., Wang, Z., Schymura, M. J., Kahn, A. & Fordyce, E. J. Cancer incidence in New York State acquired immunodeficiency syndrome patients. Am. J. Epidemiol. 154, 544–556 (2001).

    CAS  PubMed  Google Scholar 

  103. Biggar, R. J., Kirby, K. A., Atkinson, J., McNeel, T. S. & Engels, E. Cancer risk in elderly persons with HIV/AIDS. J. Acquir. Immune Defic. Syndr. 36, 861–868 (2004).

    PubMed  Google Scholar 

  104. Frisch, M., Biggar, R. J., Engels, E. A. & Goedert, J. J. Association of cancer with AIDS-related immunosuppression in adults. JAMA 285, 1736–1745 (2001).

    CAS  PubMed  Google Scholar 

  105. Haagsma, E. B. et al. Increased cancer risk after liver transplantation: a population-based study. J. Hepatol. 34, 84–91 (2001).

    CAS  PubMed  Google Scholar 

  106. Engels, E. A. & Goedert, J. J. Human immunodeficiency virus/acquired immunodeficiency syndrome and cancer: past, present, and future. J. Natl Cancer Inst. 97, 407–409 (2005).

    PubMed  Google Scholar 

  107. Stewart, T., Tsai, S. C., Grayson, H., Henderson, R. & Opelz, G. Incidence of de-novo breast cancer in women chronically immunosuppressed after organ transplantation. Lancet 346, 796–798 (1995).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We acknowledge all the scientists who made contributions to the areas of research that are reviewed here but were not cited owing to space constraints. We are grateful to T. Tlsty and the University of California, San Francisco, Breast and Prostate Specialized Programs of Research Excellence for providing human tissue sections. The authors were supported by grants from the Dutch Cancer Society (K.E.d.V.), the Serono Foundation for Advancement of Medical Science (A.E.), the National Institutes of Health, the Sandler Program in Basic Sciences, the National Technology Center for Networks and Pathways and a Department of Defense Breast Cancer Center of Excellence grant.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lisa M. Coussens.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

supplementary information

Supplementary table S1 (PDF 179 kb)

Related links

Related links

DATABASES

National Cancer Institute

Bladder cancer

breast carcinoma

colorectal carcinoma

gastrointestinal cancer

head and neck cancer

hepatocellular carcinoma

lung adenocarcinoma

melanoma

non-Hodgkin lymphoma

non-melanoma squamous cancers

ovarian cancer

pancreatic cancer

prostate cancer

OMIM

Alzheimer disease

Crohn disease

rheumatoid arthritis

FURTHER INFORMATION

Lisa M. Coussens's homepage

Glossary

Self-antigens

Antigens that are derived from normal, unaltered proteins that are expressed in tissues. The immune system does not respond to self-antigens because of immune-tolerance mechanisms; however, under certain circumstances, adaptive immune responses can be elicited towards self-antigens and result in autoimmune disease.

Regulatory T cells

T cells that can functionally suppress an immune response by influencing the activity of another cell type. Several phenotypically distinct regulatory-T-cell types might exist. The classic regulatory T cells are CD4+CD25+FOXP3+ T cells.

αβ T cells

Lymphocytes that express T-cell receptors consisting of heterodimers of α and β chains. αβ T cells recognize antigens when they are presented in association with major histocompatibility molecules.

Chronic idiopathic thrombocytopaenia

An autoimmune disease that involves autoantibody-mediated eradication of platelets, resulting in a reduced overall number of platelets. The primary clinical symptom is increased and prolonged bleeding.

Autoimmune haemolytic anaemia

An autoimmune disease that involves autoantibody-mediated premature destruction of erythrocytes, resulting in anaemia.

Systemic lupus erythematosus

A multi-system inflammatory disease that is characterized by autoantibody production and deposition of immune complexes in many organs, causing a broad spectrum of manifestations.

Fc receptors

A family of receptors that are involved in recognition of the Fc portion of antibodies. Fc receptors are expressed on the surface of various immune cells. Depending on the type of Fc receptor that is expressed, crosslinking can result in degranulation, activation of phagocytosis, and cytokine release.

Complement cascades

The complement system is made up of more than 25 components that are present in serum. Foreign antigens and immune complexes activate the complement activation cascade, resulting in formation of lytic membrane-attack complexes and liberation of potent pro-inflammatory factors.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

de Visser, K., Eichten, A. & Coussens, L. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6, 24–37 (2006). https://doi.org/10.1038/nrc1782

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc1782

This article is cited by

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