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Cancer immunotherapy via dendritic cells

Key Points

  • The molecular identification of human cancer antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Cancer vaccines aim to induce tumour-specific effector T cells that can reduce the tumour mass and to induce tumour-specific memory T cells that can control tumour relapse.

  • Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural targets for antigen delivery. DCs provide an essential link between the innate and the adaptive immune responses. DCs are at the centre of the immune system owing to their ability to control both tolerance and immune responses. These key properties of DCs render them the central candidates for antigen delivery and vaccination, including therapeutic vaccination against cancer.

  • The immune system has the potential to eliminate neoplastic cells. However, tumour cells alone are poor antigen-presenting cells (APCs). Studies with mouse models demonstrate that the generation of protective anti-tumour immune responses depends on the presentation of tumour antigens by DCs. When compared with other APCs, such as macrophages, DCs are extremely efficient at antigen presentation and inducing T cell immunity, thus explaining their nickname of 'professional APCs'.

  • Mice and humans have distinct functional subsets of DCs that generate different types of immune response. DCs are also able to mature; that is, to acquire novel functions following microbe encounters. Under steady state conditions, DCs in peripheral tissues are 'immature'. These immature DCs induce tolerance either through T cell deletion or through inducing the expansion of regulatory and/or suppressor T cells. DCs promptly respond to environmental signals and differentiate into mature DCs that can efficiently launch immune responses. It is now accepted that the adjuvant component of vaccines primarily acts by triggering DC maturation.

  • DCs are important targets for therapeutic interventions in cancer. Two themes of research are growing: first, how cancer cells alter DC physiology; and second, how we can build on the powerful properties of DCs to generate novel cancer immunotherapies (including vaccines).

Abstract

Cancer immunotherapy attempts to harness the power and specificity of the immune system to treat tumours. The molecular identification of human cancer-specific antigens has allowed the development of antigen-specific immunotherapy. In one approach, autologous antigen-specific T cells are expanded ex vivo and then re-infused into patients. Another approach is through vaccination; that is, the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural agents for antigen delivery. After four decades of research, it is now clear that DCs are at the centre of the immune system owing to their ability to control both immune tolerance and immunity. Thus, DCs are an essential target in efforts to generate therapeutic immunity against cancer.

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Figure 1: Launching the immune response.
Figure 2: DC maturation.
Figure 3: Subsets of DCs.
Figure 4: DC interaction with tumour cells: antigen capture.
Figure 5: The interaction of DCs with tumour cells: modulation of DC maturation.
Figure 6: DCs and cancer immunotherapy.

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Acknowledgements

We dedicate this Review to our long-time friend and colleague, Ralph M. Steinman, who compelled many of us to study dendritic cells and their role in disease pathophysiology and medicine. We thank all of the patients and volunteers who participated in our studies and clinical trials. We thank former and current members of the Baylor Institute for Immunology Research for their contributions to their progress. Our studies have been supported by the US National Institutes of Health (P01 CA084514, U19 AIO57234, R01 CA089440, CA078846 and CA140602), the Dana Foundation, the Susan Komen Foundation, the Baylor Health Care System; the Baylor Health Care System Foundation, the ANRS and the INSERM. K.P. holds the Michael A. Ramsay Chair for Cancer Immunology Research. Owing to space limits we could cite only a small proportion of the vast number of publications.

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Correspondence to Karolina Palucka.

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K.P. has a collaborative project and grant support from Roche. J.B. is an employee of Roche.

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Glossary

Innate immune system

Comprises the cells and molecules that defend the host from infection by other organisms in a nonspecific manner. That is, cells of the innate immune system recognize and respond to pathogens in a generic way and, unlike the adaptive immune system, do not confer immune memory.

Adaptive immune system

The part of the immune system that is mediated by antigen-specific lymphocytes and antibodies; it is highly antigen-specific and includes the development of immunological memory.

Paraneoplastic diseases

Neurological diseases induced as a result of tumour burden; generally caused by the release of tumour-derived hormones, peptides and/or cytokines, or by the misguided destruction of normal tissue by immune cells targeted against malignant cells. Most commonly present with cancers of the lung, breast, ovaries or lymphatic system (lymphoma).

CD8+ T cell

A subgroup of T lymphocytes that recognize their targets by binding to antigen that is associated with major histocompatibility class I molecules, which are present on the surface of nearly every cell. They can give rise to cytotoxic T lymphocytes, which can kill virally infected cells and tumour cells.

Antigen-presenting cells

(APCs). Cells that display foreign antigen complexes with major histocompatibility complex molecules to T cells.

Adjuvant

An agent mixed with an antigen that enhances the immune response to that antigen on vaccination.

Macrophages

Specialized monocyte-derived phagocytic cells that can capture and degrade invading microbes.

Afferent lymphatics

Vessels that enter the periphery of the lymph node and bring cells and particles from the tissue to the lymph node.

CD4+ T cells

Also known as helper T cells. A subgroup of T lymphocytes that regulate other immune cells and that are essential in B cell antibody class switching, as well as in the activation and growth of cytotoxic T cells. These cells recognize antigen that is associated with major histocompatibility complex class II molecules.

Regulatory T (TReg) cells

A subset of CD4+ T cells that maintain self-tolerance. They can express high levels of CD25 and the forkhead transcription factor FOXP3. They can secrete cytokines, such as IL-10 and TGFβ, which inhibit other T cells.

Natural killer (NK) cells

Innate immune system lymphocytes that are able to kill virally infected cells and tumour cells, particularly cells that lack the expression of major histocompatibility complex class I molecules (the presence of which inhibits NK cell cytotoxicity).

Phagocytes

White blood cells that are able to ingest foreign particles, microbes and dying cells.

Mast cells

Tissue-resident cells that contain histamine and heparin-rich granules and that mediate allergy and anaphylaxis. They are also important in the defence against pathogens.

Humoral immunity

A component of the adaptive immune system that is mediated by secreted antibodies. Antibodies are secreted from B cells that have differentiated into plasma cells.

Opsonizing antibodies

A subclass of antibodies that can bind to a pathogen or particle and at the same time bind to an Fc receptor on a phagocyte, thereby facilitating phagocytosis and pathogen clearance.

Idiotype

Individual antigenic determinants from the variable regions of the immunoglobulin heavy and light chains are referred to as idiotopes; the sum of the individual idiotopes is referred to as the idiotype.

Memory T cells

A subgroup of antigen-specific T cells that persist long after an infection has resolved. They quickly expand to large numbers of effector T cells on re-exposure to cognate antigen, thus providing immunological 'memory'.

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Palucka, K., Banchereau, J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12, 265–277 (2012). https://doi.org/10.1038/nrc3258

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