Trends in Immunology
ReviewThe pros and cons of chemokines in tumor immunology
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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Current address: Cellular and Molecular Immunology, Vrije Universiteit Brussels, Brussels, Belgium.