The pros and cons of chemokines in tumor immunology

doi:10.1016/j.it.2012.05.007

Trends in Immunology

Volume 33, Issue 10, October 2012, Pages 496-504

https://doi.org/10.1016/j.it.2012.05.007 Get rights and content

Innate and adaptive immune cells can intervene during tumor progression at different stages including initiation, angiogenesis, local spreading and distant metastasis formation. The net effect can be favorable or detrimental to tumor development, depending on the composition and activation status of the immune infiltrate. Chemokines can determine the distribution of immune cells in the tumor microenvironment and also affect stroma composition. Here we consider how a complex network of chemokines plays a key role in dictating the fate of a tumor. Although the field is in its infancy, we also highlight how targeting chemokines offers a tool to modulate the tumor environment with the aim of enhancing immune-mediated rejection of cancer.

Section snippets

Chemokines and the tumor microenvironment

Tumor progression is a multistep process based on cumulative cellular alterations. However, it is clear that this process does not exclusively depend on cancer cells, and it is also strongly influenced by the tumor microenvironment itself, which is composed of normal cells and their secreted factors. Among the soluble factors that shape the tumor microenvironment, chemokines (Box 1) have a multi-faceted role. On the one hand, they are responsible for recruiting immune cells that drive and

Chemokines and tumor control

The idea that the immune system might recognize and destroy tumor cells was conceived several decades ago. However, the concept of immune surveillance remained controversial until the discovery of the importance of interferon (IFN)-γ in promoting rejection of transplanted tumor cells [3]. This, together with improved mouse models of immunodeficiency, led to a reassessment of the role of immunity in tumor control. Mice deficient for the IFN-γ receptor, the STAT1 transcription factor (required

Chemokines and tumor progression

Transformed cells can directly hijack chemokines by acquiring expression of chemokine receptors, such as CXCR4, with the aim of colonizing distant sites, as recently reviewed [30]. However, tumors can also modify the local chemokine microenvironment as a strategy to promote their growth (Figure 1). This is for example the case of chemokines with angiogenic activity, such as CXCL1 and CXCL8, which are pivotal to generate a microenvironment with an adequate blood supply to the growing tumor

New concepts and therapeutic strategies

Impaired homing of tumor-specific T cells to tumor sites is a major limiting step in cancer immunotherapy. This is suggested by experiments and clinical trials involving adoptive cell transfer (ACT) of in vitro expanded, tumor-specific lymphocytes. In ACT for melanoma, half of the patients failed to respond to treatment even though the majority of the transferred, circulating CD8⁺ T cells showed specific antitumor activity [68]. Further studies revealed that <1% of the total transferred T cells

Concluding remarks

In the context of several human pathologies, such as inflammatory and autoimmune diseases, chemokines and their receptors are considered interesting druggable targets, and recent discoveries suggest that targeting the chemokine system may be relevant in cancer, too. The role of chemokines in cancer biology is complex because these molecules may have both pro-tumoral and antitumoral effects, with some of them playing both roles depending on undefined factors regarding tumor biology, chemokine

Acknowledgments

This work was supported by grants from the Ministry of Health (Progetto Giovani Ricercatori and Ricerca Finalizzata) and Ministry of Education (PRIN); the Istituto Superiore Sanità -Alleanza Contro il Cancro (project no. ACC8); Inserm, France, and Fondazione Cassa di Risparmio delle Provincie Lombarde (grant 5808/2007). We thank Alberto Mantovani for critical reading of the manuscript.

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Citation Excerpt :
Indeed, we demonstrate that phagocytic activity is upregulated at 24 h and expression of IL-6, IL-8, CXCL1 and TGF-β1 is upregulated by NPC EVs. Current data suggest that with progression of brain tumors, microglia and macrophages decrease phagocytic activity, increase anti-inflammatory cytokines production, increase recruitment of peripheral monocytes and increase inhibition of T cell proliferation to adopt a tumor-supportive and anti-inflammatory role [6,40,41]. In our study, we found phagocytic activity was initially upregulated, indicating that microglia exert an anti-tumor effect, but this effect diminishes with the progression of tumors.
The microenvironment of the brain has become increasingly recognized as an essential regulator in metastatic and primary brain tumors. Recent studies demonstrate that circulating tumor-derived exosomes are critical for the brain tumor microenvironment. Nasopharyngeal carcinoma (NPC), a malignant tumor of the head and neck, often invades the skull base but infrequently extends to brain parenchyma. Neurobiological communication between microglia and tumor-derived extracellular vesicles (EVs) has been extensively studied, but how NPC cells regulate the immune microenvironment in the brain remains unknown. Here, we report that NPC derived EVs lead to increased microglial phagocytosis and proliferation, and heightened levels of IL-6, IL-8, CXCL1 and TGF-β1. Analysis of microRNAs in EVs reveal that miR196a-5p is the major effector microRNA. Moreover, we demonstrate an enrichment of miR196a-5p in the plasmatic EVs of NPC patients. Further investigation demonstrated that miR196a-5p was transferred to microglia and regulated microglial structure and functions by downregulating the expression of ROCK1. Therefore, these data indicate that NPC-derived EVs are potent modulators of microglial functions in brain microenvironment. Regardless of brain colonization, EVs-mediated functional changes in microglia may be a universal phenomenon that results in the alteration of the tumor host's microenvironment in the brain.

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^*: Current address: Cellular and Molecular Immunology, Vrije Universiteit Brussels, Brussels, Belgium.

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Trends in Immunology

ReviewThe pros and cons of chemokines in tumor immunology

Section snippets

Chemokines and the tumor microenvironment

Chemokines and tumor control

Chemokines and tumor progression

New concepts and therapeutic strategies

Concluding remarks

Acknowledgments

CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis

Nature

Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

J. Exp. Med.

Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion

Science

CXC chemokines in angiogenesis of cancer

Semin. Cancer Biol.

Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity

J. Clin. Invest.

FcRgamma activation regulates inflammation-associated squamous carcinogenesis

Cancer Cell

Natural killer cell accumulation in tumors is dependent on IFN-gamma and CXCR3 ligands

Cancer Res.

Abundant expression of CXCL9 (MIG) by stromal cells that include dendritic cells and accumulation of CXCR3+ T cells in lymphocyte-rich gastric carcinoma

J. Pathol.

Cancer CXC chemokine networks and tumour angiogenesis

Eur. J. Cancer

Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells

J. Immunol.

Tumoural CXCL16 expression is a novel prognostic marker of longer survival times in renal cell cancer patients

Eur. J. Cancer

Enhanced expression and shedding of the transmembrane chemokine CXCL16 by reactive astrocytes and glioma cells

J. Neurochem.

The high expression of Fractalkine results in a better prognosis for colorectal cancer patients

Int. J. Oncol.

Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression

J. Pathol.

Maximal T cell-mediated antitumor responses rely upon CCR5 expression in both CD4(+) and CD8(+) T cells

Cancer Res.

CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells

J. Immunol.

Immune infiltration in human cancer: prognostic significance and disease control

Curr. Top. Microbiol. Immunol.

Papillary carcinoma of the thyroid: hepatocyte growth factor (HGF) stimulates tumor cells to release chemokines active in recruiting dendritic cells

Am. J. Pathol.

Regulation of the trafficking of tumour-infiltrating dendritic cells by chemokines

Semin. Cancer Biol.

CXCL17 and ICAM2 are associated with a potential anti-tumor immune response in early intraepithelial stages of human pancreatic carcinogenesis

Gastroenterology

Orchestrating the orchestrators: chemokines in control of T cell traffic

Nat. Immunol.

CC-chemokine ligand 17 gene therapy induces tumor regression through augmentation of tumor-infiltrating immune cells in a murine model of preexisting CT26 colon carcinoma

Int. J. Cancer

Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures

J. Clin. Oncol.

Antigen-driven oligoclonal expansion of tumor-infiltrating B cells in infiltrating ductal carcinoma of the breast

J. Immunol.

Helper B cells promote cytotoxic T cell survival and proliferation independently of antigen presentation through CD27/CD70 interactions

J. Immunol.

T cell costimulation by chemokine receptors

Nat. Immunol.

Targeting the function of IFN-gamma-inducible protein 10 suppresses ongoing adjuvant arthritis

J. Immunol.

The lymphoid chemokine CCL21 costimulates naive T cell expansion and Th1 polarization of non-regulatory CD4+ T cells

Cell. Immunol.

A role for CXCR2 in senescence, but what about in cancer?

Cancer Res.

Homeostatic chemokine receptors and organ-specific metastasis

Nat. Rev. Immunol.

Membrane type 1-matrix metalloproteinase is regulated by chemokines monocyte-chemoattractant protein-1/ccl2 and interleukin-8/CXCL8 in endothelial cells during angiogenesis

J. Biol. Chem.

CXCR1 and CXCR2 silencing modulates CXCL8-dependent endothelial cell proliferation, migration and capillary-like structure formation

Microvasc. Res.

Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells

Nature

Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy?

Lancet Oncol.

Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival

Nat. Med.

NK depletion results in increased CCL22 secretion and Treg levels in Lewis lung carcinoma via the accumulation of CCL22-secreting CD11b+CD11c+ cells

Review
The pros and cons of chemokines in tumor immunology