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  • Review Article
  • Published:

Paradoxical roles of the immune system during cancer development

Nature Reviews Cancer volume 6, pages 24–37 (2006)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Department of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    Karin E. de Visser

  2. Cancer Research Institute, San Francisco, 2340 Sutter Street, San Francisco, 94143, California

    Alexandra Eichten & Lisa M. Coussens

  3. Department of Pathology, University of California, San Francisco, 2340 Sutter Street, San Francisco, 94143, California

    Lisa M. Coussens

  4. Comprehensive Cancer Center, University of California, San Francisco, 2340 Sutter Street, San Francisco, 94143, California

    Lisa M. Coussens

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  1. Karin E. de Visser
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Correspondence to Lisa M. Coussens.

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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

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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.

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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

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