Key Points
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The immune response against cancer is tightly regulated through a set of stimulatory and inhibitory molecules expressed by cancer cells, stromal cells (including APCs) and haematopoietic cells in the tumour microenvironment.
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Expression of inhibitory members of the co-stimulatory B7 family, such as B7-H1 and B7-H4, is often up-regulated in the tumour microenvironment by local factors including cytokines.
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Inhibitory B7 molecules mediate various mechanisms to evade tumour-antigen-specific T-cell immunity, including T-cell apoptosis, anergy and exhaustion, forming a molecular shield to protect tumour cells from lysis, and functional modulations of antigen-presenting cells and regulatory T cells.
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Expression of inhibitory B7 molecules in the tumour microenvironment correlates with poor prognosis in several types of human cancer. Therefore, these molecules might be potential biomarkers to predict therapeutic outcome.
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Blockade of signalling through the inhibitory B7 molecules is a promising strategy that might work alone or in combination with other modalities to improve current tumour therapies.
Abstract
The B7 family consists of activating and inhibitory co-stimulatory molecules that positively and negatively regulate immune responses. Recent studies have shown that human and rodent cancer cells, and stromal cells and immune cells in the cancer microenvironment upregulate expression of inhibitory B7 molecules and that these contribute to tumour immune evasion. In this Review, we focus on the roles of these B7 molecules in the dynamic interactions between tumours and the host immune system, including their expression, regulation and function in the tumour microenvironment. We also discuss novel therapeutic strategies that target these inhibitory B7 molecules and their signalling pathways to treat human cancer.
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Acknowledgements
We would like to thank our former and current trainees and 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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Glossary
- Tumour-associated antigens
-
(TAAs). Antigens that are expressed by tumour cells. These belong to three main categories: tissue-differentiation antigens, which are also expressed by non-malignant cells; mutated or aberrantly expressed molecules; and cancer testis antigens, which are normally expressed only by spermatocytes and occasionally in the placenta.
- Myeloid-derived suppressor cells
-
A population of cells that comprises mature and immature myeloid cells. They are expanded and/or activated during an inflammatory immune response. Through direct interactions and secreted components, they inhibit T-cell function.
- Regulatory T (TReg) 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 known as TReg cells.
- Two-signal model
-
The concept that both the MHC–peptide complex (signal 1) and co-stimulatory signals delivered by B7-family molecules expressed by antigen-presenting cells (signal 2) are required for T-cell activation. The absence of signal 2 results in the induction of T-cell anergy or deletion.
- Cytotoxic T-lymphocyte-antigen 4
-
(CTLA4). After engagement by CD80 or CD86 on antigen-presenting cells, CTLA4 signalling in activated T cells induces cell-cycle arrest, decreases cytokine production and inhibits T-cell responses. CD4+CD25+ TReg cells constitutively express CTLA4.
- Myeloid DCs
-
A subset of dendritic cells (DCs) that are lineage-negative, HLA-DR+CD11c+ (in humans) mononuclear cells with a monocytoid appearance. Human myeloid DCs might be derived from myeloid precursors (for example, monocytes, macrophages and CD11c+ precursors).
- Plasmacytoid DCs
-
A subset of dendritic cells (DCs) that are lineage negative, HLA-DR+CD11c− (in humans) mononuclear cells with a microscopic appearance similar to plasmablasts. Plasmacytoid DCs are the main producers of type I interferon.
- Indoleamine 2,3-dioxygenase
-
(IDO). An intracellular haem-containing enzyme that catalyses the oxidative catabolism of tryptophan. Insufficient availability of tryptophan can lead to T-cell apoptosis and anergy.
- Arginase
-
An enzyme that converts L-arginine into l-ornithine and urea.
- Danger signals
-
Agents that alert the immune system to stress, usually by interacting with Toll-like receptors and other pattern-recognition receptors, and thereby promote the generation of innate and adaptive immune responses. Danger signals can be associated with microbial invaders (exogenous danger signals) or produced by damaged cells (endogenous danger signals).
- Anergy
-
A state of non-responsiveness to antigen. Anergic T or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.
- Exhaustion
-
An 'operational' definition that refers to the loss of antigen-specific T-cell responses in vivo after prolonged or repetitive stimulation with antigen. This has been best observed in a model of infection with lymphocytic choriomeningitis virus Docile strain, for which the exact mechanism is still not understood.
- Small interfering RNA
-
Double-stranded RNAs (dsRNAs) with sequences that precisely match a given gene are able to 'knock down' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript. The two most common forms of dsRNAs used for gene silencing are short — usually 21-bp long — small interfering RNAs (siRNAs) or the plasmid-delivered short hairpin RNAs (shRNAs).
- Antisense oligonucleotides
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Short, gene-specific sequences of nucleic acids that are of the opposite strand (complementary) to the targeted mRNA. Classical antisense oligonucleotides target specific strands of RNA within a cell, thereby preventing translation of these RNAs.
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Zou, W., Chen, L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8, 467–477 (2008). https://doi.org/10.1038/nri2326
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DOI: https://doi.org/10.1038/nri2326
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