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  • Review Article
  • Published:

Chemokines: agents for the immunotherapy of cancer?

Nature Reviews Immunology volume 2, pages 175–184 (2002)Cite this article

Key Points

  • Chemokines are small, cytokine-like, secreted proteins (8–11 kDa) that regulate leukocyte transport by mediating the adhesion of leukocytes to endothelial cells, the initiation of transendothelial migration and tissue invasion. To date, we know of 24 human CC chemokines (CCL1–CCL28), 15 human CXC chemokines (CXCL1–16) and one each of the CX3C and C chemokine subclasses, which are represented by fractalkine (CX3CL1) and lymphotactin (XCL1), respectively.

  • The role of chemokines in tumour biology is complex. Besides their action on haematopoietic cells, recent studies have shown that chemokines also induce distinct effects in non-haematopoietic cells such as stromal and solid tumour cells. Chemokines can act as autocrine or paracrine growth factors, induce angiogenesis or angiostasis, regulate metastasis and have a role in the host's immune response against tumour cells.

  • Findings in experimental tumour models have shown that the introduction of chemokines such as CCL1 (I-309), CCL2 (monocyte chemoattractant protein-1; MCP-1), CCL3 (macrophage inflammatory protein-1a; MIP-1a), CCL5 (regulated upon activation normal T cell expressed and secreted, RANTES), CCL16 (human β CC chemokine 4; HCC-4), CCL19 (MIP-3b), CCL20 (MIP-3a), CCL21 (6Ckine), CXCL10 (interferon-γ inducible protein-10, IP-10) and XCL1 (lymphotactin) alone can induce tumour regression and immunity to subsequent tumour challenge.

  • Chemokines alone seem to show limited antitumour efficacy. However, new approaches are being developed that combine a chemoattractant (e.g. CCL19, CCL21, CXCL9, CXCL10, CXCL12 and XCL1) together with cytokines (interleukin-2 (IL-2), IL-12, granulocyte–macrophage colony-stimulating factor (GM-CSF)), which are known for their stimulating properties on T cells, natural killer (NK) cells or tumour antigen-pulsed dendritic cells (DCs).

  • Chemokines might act as potent natural adjuvants for experimental antitumour immunotherapy. Their combination with tumour peptide-pulsed DCs and direct coupling to tumour antigen or immunostimulatory cytokines results in synergistic antitumour activity. This is a way of reducing toxic side effects.

  • The combination of tumour antigen-releasing therapies (chemotherapy and radiation therapy) with chemokine delivery to sites of tumour antigen exposure, and the in vivo administration of 'DC-poietins' such as FTL3 ligand or GM-CSF and other activation molecules (IL-2, IL-12, CD40L and CpG), offers promising strategies to induce strong and long-lived antitumour immunity. However, side effects such as the induction of autoimmunity and the concept of leukocyte-mediated tumour-cell proliferation/survival and invasion should not be overlooked.

Abstract

Chemokines, a superfamilly of small cytokine-like molecules, regulate leukocyte transport in the body. In recent years, we have witnessed the transition of immunotherapeutic strategies from the laboratory to the bedside. Here, we review the role of chemokines in tumour biology and the development of the host's anti-tumour defence. We summarize the current knowledge of chemokine-receptor expression by relevant cellular components of the immune system and the role of their ligands in the organization of the antitumour immune response. Finally, we discuss recent findings which indicate that chemokines have therapeutic potential as adjuvants or treatments in antitumour immunotherapy, as well as remaining questions and perspectives for translating experimental evidence into clinical practice.

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Figure 1: Chemokines orchestrate immune responses.
Figure 2: Concepts in the immunotherapy of cancer patients.

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Acknowledgements

We thank E. Bünemann for assistance, and S. Wagner and M. C. Dieu-Nosjean for discussions. We apologize to those colleagues whose work was not discussed due to space restrictions.

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Authors and Affiliations

  1. Departments of Dermatology and Radiation Oncology, Heinrich-Heine-University, Düsseldorf, D-40225, Germany

    Bernhard Homey & Anja Müller

  2. Eos Biotechnology, South San Francisco, 94080, California, USA

    Albert Zlotnik

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Correspondence to Bernhard Homey.

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DATABASES

LocusLink

CCL3

CCL7

CCL20

CD4

CD8

CXCL1

CXCL10

CXCL15

CX3CL1

CTACK

ENA-78

GM-CSF

I-309

IL-2

IL-8

IL-12

lymphotactin

MIG

RANTES

SDF-1

TARC

TNF-α

VEGF

 OMIM

breast cancer

Glossary

ANGIOSTATIC

Angiostatic factors impair the formation of new capillary blood vessels, a process termed angiogenesis. Angiogenesis involves the proliferation, migration and differentiation of endothelial cells.

MATRIX METALLOPROTEINASES (MMPs).

The catalytic activity of these enzymes is important in normal biology because of their role in morphogenesis, homeostasis and repair, and they are also implicated in inflammation and disease. Beyond their role in the turnover and degradation of extracellular-matrix proteins, MMPs also process, activate and deactivate various soluble factors.

ACTIN POLYMERIZATION

Part of the intracellular cytoskeletal rearrangement that is the prerequisite for cell motility and migration.

TNM CLASSIFICATION

A staging system for cancer patients. T1–4 indicates primary tumour size. N0 indicates no evidence of lymph node metastasis, N+ indicates regional lymph node metastasis, M0 indicates no distant metastasis and M1 indicates distant metastasis.

TYPE 1 MEMORY T CELLS

(TH1 cells). These are CD4+ T-helper cells, which predominantly produce interferon-γ.

DC-POIETIN

A factor/cytokine that is able to expand the number of circulating dendritic cells.

MICROARRAY ANALYSES

A powerful tool for identifying genes that are associated with complex biological phenomena. Microarrays contain human cDNAs of known and unknown sequences, which are printed on glass slides using high-speed robotics. These DNA 'chips' are used to quantitatively monitor differential expression of the human genes using a highly sensitive two-colour hybridization assay.

PROTEOMICS

A promising approach for the identification of proteins and biochemical pathways that are involved in tumorigenesis. In an effort to discover such tumour-associated proteins and pathways, tumour protein lysates are subjected to two-dimensional electrophoresis and mass spectrometry and are analysed using large protein databases.

FTL3 LIGAND

A cytokine that binds to the FLT3/FLK2 tyrosine kinase receptor, stimulates the proliferation of defined subpopulations of bone-marrow cells and increases the number of circulating dendritic cells.

CD40 LIGAND

(CD40L, CD154). A member of the tumour-necrosis factor family of cell-surface molecules and mediates contact-dependent signals that are delivered by CD4+ T-helper cells to CD40+ target cells.

PREDC2

(pDC2/IPC (type 1 interferon-producing cell)). Represents a subset of immature CD4+CD3−CD11c− plasmacytoid dendritic cells, which are also known as natural IPCs.

CPG MOTIFS

Immunostimulatory sequences of DNA that are potent mediators of TH1 and cytotoxic T-lymphocyte responses to antigens.

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Homey, B., Müller, A. & Zlotnik, A. Chemokines: agents for the immunotherapy of cancer?. Nat Rev Immunol 2, 175–184 (2002). https://doi.org/10.1038/nri748

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