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Chemokines: Small, but Powerful Regulators of the Immune System—Potential Anti-tumor Targets and Reagents

The development of the immune system and the activation of specific immune responses are dependent on many complex interactions. These interactions are mediated by specific surface receptors on the cell and the combination of soluble factors and cell-associated ligands present at each particular instant and location. Soluble factors are responsible for the attraction and trafficking of immune cells to lymphoid organs and sites of infection, the maturation and differentiation of lymphoid cells, and for directing the immune system towards a cellular or humoral response. The proper combination and sequence of factors result in the development of a functional immune system and the generation and regulation of an appropriate immune response to pathogen challenge. The inappropriate sequence and combination of immune modulators may lead to tolerance, anergy, and autoimmunity. Chemokines, first identified as key chemotactic factors involved in the recruitment of neutrophils to sites of inflammation, are now emerging as critical mediators of many aspects of the immune system. A rapidly expanding family of genes, chemokines are known to act on lymphocytes, granulocytes, macrophages, and dendritic cells, among other cell types (1–3). Chemokines and their receptors function in chemotaxis during inflammation, lymphocyte recirculation, directed migration to and within lymphoid organs, and leukocyte and lymphocyte maturation (1–3). They have also been implicated in wound healing and both angiogenesis and angiostasis (1–3). Given the powerful and diverse properties of chemokines, it is not surprising that their role and potential therapeutic use in cancer is attracting attention. Although early in the field, Drs. Flanagan and Kaufman in “Chemokines and Cancer” review the current state of knowledge of chemokine function, as well as provide a glimpse of future utilization of chemokines for cancer therapy and immunotherapy. Particularly relevant are the angiogenic/angiostatic properties of the CXC chemokines as it relates to tumor growth and metastatic spread. Further, the ability of various chemokines to attract effector lymphoid cells makes them attractive reagents for incorporation into tumor cells for immunotherapeutic vaccines for cancer. It is the identification and understanding of the specific soluble and cell surface immune modulators that holds the key for our successful manipulation of the immune response to diseases such as cancer. The full spectrum and temporal expression of molecules involved in the generation and attenuation of the immune response will be of enormous value in the prevention and treatment of infectious, autoimmune, and neoplastic