Trends in Immunology
Volume 33, Issue 10, October 2012, Pages 496-504
Journal home page for Trends in Immunology

Review
The pros and cons of chemokines in tumor immunology

https://doi.org/10.1016/j.it.2012.05.007Get 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.

References (104)

  • S. Sozzani

    The viral chemokine macrophage inflammatory protein-II is a selective Th2 chemoattractant

    Blood

    (1998)
  • J.T. Stine

    KSHV-encoded CC chemokine vMIP-III is a CCR4 agonist, stimulates angiogenesis, and selectively chemoattracts TH2 cells

    Blood

    (2000)
  • F.R. Balkwill et al.

    Cancer-related inflammation: common themes and therapeutic opportunities

    Semin. Cancer Biol.

    (2012)
  • H. Roca

    CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization

    J. Biol. Chem.

    (2009)
  • R.D. Loberg

    CCL2 is a potent regulator of prostate cancer cell migration and proliferation

    Neoplasia

    (2006)
  • B. Huang

    CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers

    Cancer Lett.

    (2007)
  • Y. Sawanobori

    Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice

    Blood

    (2008)
  • L. Yang

    Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis

    Cancer Cell

    (2008)
  • Z. Granot

    Tumor entrained neutrophils inhibit seeding in the premetastatic lung

    Cancer Cell

    (2011)
  • A. Sparmann et al.

    Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis

    Cancer Cell

    (2004)
  • A. Di Stasi

    T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model

    Blood

    (2009)
  • H.D. Cunningham

    Expression of the C-C chemokine receptor 7 mediates metastasis of breast cancer to the lymph nodes in mice

    Transl. Oncol.

    (2010)
  • J. Vandercappellen

    The role of CXC chemokines and their receptors in cancer

    Cancer Lett.

    (2008)
  • C. Gebhardt

    S100A8 and S100A9 in inflammation and cancer

    Biochem. Pharmacol.

    (2006)
  • B.Z. Qian

    CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis

    Nature

    (2011)
  • B. Molon

    Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

    J. Exp. Med.

    (2011)
  • R.D. Schreiber

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

    Science

    (2011)
  • P. Romagnani

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

    J. Clin. Invest.

    (2001)
  • M. Wendel

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

    Cancer Res.

    (2008)
  • H. Ohtani

    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.

    (2009)
  • S. Matsumura

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

    J. Immunol.

    (2008)
  • A. Ludwig

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

    J. Neurochem.

    (2005)
  • M. Ohta

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

    Int. J. Oncol.

    (2005)
  • D. Berghuis

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

    J. Pathol.

    (2010)
  • A. Gonzalez-Martin

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

    Cancer Res.

    (2011)
  • Y.C. Nesbeth

    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.

    (2010)
  • W.H. Fridman

    Immune infiltration in human cancer: prognostic significance and disease control

    Curr. Top. Microbiol. Immunol.

    (2011)
  • N. Hiraoka

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

    Gastroenterology

    (2010)
  • S.K. Bromley

    Orchestrating the orchestrators: chemokines in control of T cell traffic

    Nat. Immunol.

    (2008)
  • N. Kanagawa

    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

    (2007)
  • M.C. Dieu-Nosjean

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

    J. Clin. Oncol.

    (2008)
  • J.A. Coronella

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

    J. Immunol.

    (2002)
  • S. Deola

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

    J. Immunol.

    (2008)
  • B. Molon

    T cell costimulation by chemokine receptors

    Nat. Immunol.

    (2005)
  • I. Salomon

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

    J. Immunol.

    (2002)
  • J.C. Acosta et al.

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

    Cancer Res.

    (2009)
  • A. Zlotnik

    Homeostatic chemokine receptors and organ-specific metastasis

    Nat. Rev. Immunol.

    (2011)
  • A. Facciabene

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

    Nature

    (2011)
  • T.J. Curiel

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

    Nat. Med.

    (2004)
  • A.W. Mailloux

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

    Int. J. Cancer

    (2010)
  • Cited by (95)

    • MiR196a-5p in extracellular vesicles released from human nasopharyngeal carcinoma enhance the phagocytosis and secretion of microglia by targeting ROCK1

      2022, Experimental Cell Research
      Citation Excerpt :

      Furthermore, a recent study suggests that exosomes derived from NPC cells induce macrophages to secrete IL-6 to promote tumorigenesis [37]. IL-8, in contrast, is necessary for the generation of a microenvironment that promotes angiogenesis and immune suppression [40,43]. CXCL1 and TGF-β1 also play an immunosuppressive role in the tumor microenvironment.

    View all citing articles on Scopus
    *

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

    View full text