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Immunosuppressive networks in the tumour environment and their therapeutic relevance

Key Points

  • The pathological interactions between cancer cells and host immune cells in the tumour microenvironment create an immunosuppressive network that promotes tumour growth, protects the tumour from immune attack and attenuates immunotherapeutic efficacy.

  • Poor tumour-associated antigen (TAA)-specific immunity is not simply due to a passive process whereby adaptive immunity is shielded from detecting TAAs. There is an active process of 'tolerization' taking place in the tumour microenvironment.

  • Tumour tolerization is the result of imbalances in the tumour microenvironment, including alterations in antigen-presenting-cell subsets, co-stimulatory and co-inhibitory molecule alterations and altered ratios of effector T cells and regulatory T cells.

  • Human tumorigenesis is a slow process that can occur over several years and in this respect is similar to chronic infection. The lack of an acute phase in the course of tumorigenesis might profoundly shape T-cell immune responses, including the quality of antigen release, T-cell priming and activation.

  • Current immunotherapies often target patients with advanced-stage tumours, which have high levels of inflammatory molecules, cytokines, chemokines, tumour-infiltrating T cells, dendritic cells and macrophages. It is arguable whether we need to incorporate more of these components into tumour treatments.

  • Immune tolerization is predominant in the immune system in patients with advanced-stage tumours. It is time to consider combinatorial tumour therapies, including those that subvert the immune-tolerizing conditions within the tumour.

Abstract

It is well known that many tumours are potentially immunogenic, as corroborated by the presence of tumour-specific immune responses in vivo. Nonetheless, spontaneous clearance of established tumours by endogenous immune mechanisms is rare. Therefore, the focus of most cancer immunotherapies is to supplement essential immunogenic elements to boost tumour-specific immunity. Why then has tumour immunotherapy resulted in a generally poor clinical efficiency? The reason might lie in the increasingly documented fact that tumours develop diverse strategies that escape tumour-specific immunity.

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Figure 1: An aberrant tumour microenvironmental molecule pattern and dendritic cells.
Figure 2: Imbalance of co-stimulatory and co-inhibitory molecules on antigen-presenting cells within the tumour microenvironment.
Figure 3: Imbalances in antigen-presenting-cell subsets and tumour immunity.
Figure 4: Specific recruitment and tumour immune evasion.
Figure 5: Imbalances in antigen-presenting-cell subsets and tumour vascularization.
Figure 6: T-cell-subset imbalance and tumour-specific immunity.

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Acknowledgements

I would thank my father, Y. Zou for his precious support, M. von Herrath, V. Cerundolo and C.J.M. Melief for critical reading the manuscript, and the collaborators for their intellectual input and hard work. The review focuses on human tumour immunopathogenesis; owing to the plethora of literature related to this topic, a complete and extensive review is extremely challenging. I apologize in advance for any inadvertent omission. The work described in this review was supported by grants from the United States National Institutes of Health and the Department of Defense.

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DATABASES

Entrez Gene

ARG1

B7.1

B7.2

B7-H1

CCL22

CCR4

CCR7

CD62L

COX2

CRP

CTLA4

CXCL12

CXCR4

GM-CSF

IFNγ

IL-10

IL-12

IL-4

IL-6

LIGHT

M-CSF

NOS2

PGE2

TGFβ

TLR9

VEGF

National Cancer Institute

breast cancer

melanoma

ovarian cancer

prostate cancer

renal-cell cancer

FURTHER INFORMATION

Weiping Zou's lab

Glossary

TOLERANCE

A state in which the immune system does not mount effective immune responses against specific antigens.

ANTIGEN-PRESENTING CELLS

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 antigen-presenting cells. Dendritic cells are the most potent of these.

EFFECTOR T CELLS

T cells that exert a cytolytic function following engagement of their T-cell antigen receptor on target cells. CTLs express the co-receptor CD8 and recognize antigenic peptides that are presented by human leukocyte antigen class I molecules.

NATURAL KILLER CELLS

Natural killer cells are a type of cytotoxic lymphocyte that can be distinguished from CD8+ T cells by their lack of rearrangement of T-cell receptor genes. They have abundant granule-containing cytoplasm, induce target-cell death through direct contact or by cytokine production, and confer innate immunity.

MYELOID DENDRITIC CELLS

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

PLASMACYTOID DENDRITIC CELLS

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

B7-H1

A recently defined B7 family member that is found to be expressed in human epithelial tumours, and can be induced in antigen-presenting cells and in non-lymphoid organs. PD-1 is the identified receptor. Experimental evidence indicates the existence of an unidentified receptor for B7-H1. B7-H1 can mediate an inhibitory role as well as stimulatory role in T-cell-mediated immune responses.

INDOLEAMINE 2,3-DIOXYGENASE

An intracellular haeme-containing enzyme that catalyses oxidative catabolism of tryptophan.

T HELPER 1 CELLS AND T HELPER 2 CELLS

Two functionally defined CD4+ T-cell subsets. T helper 1 (TH1) cells predominantly produce interferon-γ, and support cellular immunity. TH2 cells predominantly produce interleukin-4, and support humoral immunity.

TUMOUR ASCITES

An accumulated fluid in the peritoneum due to cancer. In some cancers, the ascites fluid contains viable tumour cells, immune cells and soluble factors. Tumour ascites is an accessible tumour environment for research.

REGULATORY T CELLS

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

NOD/SCID MICE

Mice that do not have T cells or B cells. Tumour cells can be grown in these mice without rejection.

B7-H4

A newly defined B7 family member that is found to be expressed in human ovarian epithelial tumours, non-lymphoid organs and antigen-presenting cells within the tumour microenvironment. The receptor remains to be identified. The B7-H4 fusion protein can mediate a profound inhibitory role in T-cell-mediated immune responses.

ANERGY

A state in which lymphocytes can not respond to antigen-specific and non-specific stimulation.

CYTOTOXIC T-LYMPHOCYTE-ASSOCIATED PROTEIN 4

Following engagement by B7.1 or B7.2 on antigen-presenting cells, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) signalling in activated T cells induces cell-cycle arrest, and reduces cytokine production, and diminishes T-cell responses. CD4+CD25+ regulatory T cells constitutively express CTLA4.

ALLOGENEIC

Allogeneic tissues or cells are genetically different from the host and can elicit an immune response when transplanted into immune-competent hosts.

DANGER SIGNALS

Triggers that are associated with host-cell damage. These 'danger signals' induce the activation of antigen-presenting cells. The danger signals could be intracellular components that are released when cells are damaged, such as DNA and proteins, or inflammatory molecules and cytokines, such as interferon-γ.

CpG OLIGONUCLEOTIDES

Synthetic oligodeoxynucleotides (CpG-ODNs) that contain CpG motifs that are similar to those found in bacterial DNA that can stimulate an immune response. These CpG-ODNs have various potential therapeutic uses.

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Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer 5, 263–274 (2005). https://doi.org/10.1038/nrc1586

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