Chemokines produced by malignant cells are often angiogenic. Angiogenesis promotes tumor cell growth and survival and influences cancer cell migration and metastasis. Less appreciated perhaps, is the role of chemokines in the attraction of immune cells to the tumor site. The infiltration of circulating leukocytes to the tumor is obviously facilitated by angiogenic activity, but can also occur via extravasation and migration through the surrounding tissue.1,2
The numbers and types of leukocytes present in the infiltrate is related to the chemokines produced by both the tumor cells and tissue stromal cells located at the tumor site. For example, breast, cervical, and pancreatic tumors, as well as sarcomas and gliomas produce CC chemokines that are important mediators of macrophage and lymphocyte infiltration in those tumors.3,4 In ovarian cancer, both CC and CXC chemokines are important for the infiltration of CD8+ T cells and macrophages.5 Concomitant expression of CCR1 on the tumor-infiltrating leukocytes (TILs) in ovarian tumors has also been described.6 Characterization of specific chemokine receptors expressed on TILs is often hampered by chemokine receptor down-regulation either by excessive quantities of chemokines and pro-inflammatory cytokines produced by the tumor, or by the hypoxic environment of many solid tumors.7,8
|Figure 1. Chemokine receptor expressing CD8+ T cells and monocytes are drawn to the tumor site by chemokines released by tumor cells, resident tissue macrophages, and native stromal cells.
The influx of TILs to the tumor site enhances the potential for anti-tumor immune responses. However, the suppressive environment of the tumor is hypothesized to down-regulate host anti-tumor immunity. A role for the chemokines produced in the tumor microenvironment in mediating the suppression of host anti-tumor immunity is beginning to emerge.1,2 First, in an autocrine or paracrine manner, chemokines may stimulate rapid tumor growth that cannot be effectively eradicated by the host immune response. Second, investigations have shown that TILs often exhibit a polarized Th2 phenotype.3 Chemokines such as MCP-1/CCL2 can actively contribute to the polarization of the host immune response to a Type II inflammatory response.9 Such Type II responses may not only augment the growth and survival of the tumor, but may also suppress cell-mediated immunity.3 Third, chemokines in the tumor microenvironment have been shown to suppress the maturation and function of dendritic cells thereby inhibiting antigen presentation.10 Finally, paracrine production of chemokines that stimulate CCR5 on TILs induces TIL cell death.11
Manipulation of the chemokine microenvironment has emerged as a potential therapeutic strategy in treating malignant tumors. The presence of TILs and macro-phages, in particular, have been correlated with poor prognosis in several tumor models.12 In addition to the suppressive activities of Th2 TILs, chemokines such as MCP-1/CCL2, MIP-1ß/CCL4, and RANTES/CCL5 produced by TILs stimulate the production of matrix metalloproteinases (MMPs) such as MMP-9.13 MMPs are up-regulated in a variety of tumors and can enhance angiogenesis and tumor cell migration and invasion, making MMPs a potential target for cancer therapy as well.14 It is believed that the use of chemokine receptor antagonists can induce tumor growth arrest or apoptosis, prevent metastatic spread, and even inhibit immuno-suppressive macrophage or Th2 cell infiltration.
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