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Nature Reviews Immunology
  • Review Article
  • Published:

Regulatory T cells, tumour immunity and immunotherapy

Nature Reviews Immunologyvolume 6, pages295–307 (2006)Cite this article

Key Points

  • An active process of tolerization takes place in the tumour microenvironment. Induction of trafficking, differentiation and expansion of regulatory T cells is a crucial tumour immune-tolerizing mechanism and is also one of the main obstacles tempering successful immunotherapy.

  • Interactions between cancer cells and host immune cells in the tumour microenvironment create an immunosuppressive network. Regulatory T cells are substantially recruited to the tumour through tumour environmental chemokine(s).

  • Tumour environmental regulatory T cells might use multiple suppressive mechanisms to reduce tumour-associated antigen (TAA)-specific T-cell immunity. A novel suppressive mechanism is that regulatory T cells convey suppressive capacity to antigen-presenting cells (APCs) through induction of B7-H4 expression.

  • CD4+CD25+ regulatory T cells (TReg cells) accumulate in the tumour environment and reduce TAA-specific immunity, and their presence can be used to predict patient survival. Data from clinical trials of depletion of regulatory T cells are immunologically and therapeutically interesting.

  • Current immunotherapeutic and vaccine regimens including interleukin-2 (IL-2) administration and APC vaccination could potentially promote regulatory T-cell functionin vivo and need careful re-evaluation with regard to beneficial versus detrimental effects. IL-2 could be therapeutically replaced by other common cytokine-receptor γ-chain cytokines.

  • Depletion of regulatory T cells or reduction of regulatory T-cell suppressive activity are two promising strategies that could either work alone or in combination to improve current tumour therapies. It is time to consider combinational immunotherapy, including reverting suppressive mechanisms, supplementing active immune elements and suppressing tumour growth and angiogenesis.

Abstract

Tumours express a range of antigens, including self-antigens. Regulatory T cells are crucial for maintaining T-cell tolerance to self-antigens. Regulatory T cells are thought to dampen T-cell immunity to tumour-associated antigens and to be the main obstacle tempering successful immunotherapy and active vaccination. In this Review, I consider the nature and characteristics of regulatory T cells in the tumour microenvironment and their potential multiple suppressive mechanisms. Strategies for therapeutic targeting of regulatory T cells and the effect of regulatory T cells on current immunotherapeutic and vaccine regimens are discussed.

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Figure 1: Regulatory T cells in the tumour microenvironment.
Figure 2: Possible suppressive mechanisms of tumour environmental regulatory T cells.
Figure 3: Therapeutic targeting of suppressive mechanisms including regulatory T cells.

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Acknowledgements

I thank J. L. Wilson for discussing and shaping this manuscript, and my collaborators for their intellectual input and hard work. The work described in this Review was supported by grants from the United States National Institutes of Health and the United States Department of Defense.

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  1. Department of Surgery, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, 48109-0346, Michigan, USA

    Weiping Zou

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Glossary

Regulatory T cells

A T-cell population that can functionally suppress an immune response by influencing the activity of another cell type. Several phenotypically distinct regulatory T-cell populations exist. The classic regulatory T cells are CD4+CD25+FOXP3+ T cells (TReg cells).

Antigen-presenting cells

(APCs). Cells that uptake, process and present antigen to other immune cells to initiate and activate immune responses. Monocytes, macrophages, dendritic cells and B cells are APCs. Dendritic cells are the most potent APCs.

Cytotoxic T-lymphocyte-associated antigen 4

(CTLA4). Following ligation by B7.1 (CD80) or B7.2 (CD86) on APCs, CTLA4 signalling in activated T cells induces cell-cycle arrest, reduces cytokine production and diminishes T-cell responses. TReg cells constitutively express CTLA4.

FIGO stages

Based on the International Federation of Gynaecology and Obstetrics (FIGO), ovarian cancer is classified into four surgicopathological stages: stage I, the tumour is confined to the ovaries; stage II, the tumour is confined to the pelvis; stage III, the tumour is confined to the abdomen; and stage IV, the tumour extends outside the abdominal cavity.

Severe combined immunodeficiency

(SCID). SCID mice do not have B cells or T cells. Tumour cells can be grown in these mice without rejection.

Plasmacytoid dendritic cells

A subset of dendritic cells that is lineage−HLA-DR+CD11c− mononuclear cells with a microscopic appearance similar to plasmablasts. Plasmacytoid dendritic cells are the main producers of type I interferon.

Central memory T cells

Antigen-experienced CD8+ T cells that lack immediate effector function but are able to mediate rapid recall responses. They also rapidly develop the phenotype and function of effector-memory cells after restimulation with antigen. Central memory T cells retain the migratory properties of naive cells and therefore circulate through secondary lymphoid organs.

Myeloid dendritic cells

A subset of dendritic cells that is lineage−HLA-DR+CD11c+ mononuclear cells with a monocytoid appearance. Human myeloid dendritic cells might develop from myeloid precursors (for example, monocytes, macrophages and CD11c+ precursors).

LAGE-1 and NY-ESO-1

LAGE-1 and NY-ESO-1 (New York oesophageal squamous-cell carcinoma 1) are two cancer- and testis-specific antigens that show 94% sequence identity. The genes encoding LAGE-1 and NY-ESO-1 are both located on chromosome Xq28 and are frequently co-expressed. LAGE-1 and NY-ESO-1 have been shown to be expressed in 25?50% of various tumour types, such as melanoma, breast carcinoma, prostate and bladder cancers.

Natural killer cell

Cytotoxic lymphocytes that are distinguished from CD8+ T cells by their lack of rearrangement of T-cell receptor genes. They have abundant granule-containing cytoplasm, and their functions are cell killing and cytokine production.

Indoleamine 2,3-dioxygenase

(IDO). An intracellular haem-containing enzyme that catalyses oxidative catabolism of tryptophan.

B7-H4

A newly defined B7-family member. B7-H4 fusion protein inhibits T-cell-mediated immune responses. The receptor, regulation and detailed function remain to be defined.

RECIST criteria

A set of criteria, designated the response evaluation criteria in solid tumours.

Objective clinical response

Based on the International Union Against Cancer and World Health Organization, an objective clinical response to treatment is defined as a 50% reduction in the sum of the products of the perpendicular diameters of all lesions without the 25% growth of any lesion or the appearance of new lesions. RECIST defines an objective clinical response as a 30% reduction in the sum of the maximum diameters of lesions, along with the appearance of no new or progressive lesions.

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