Clinical utilization of chemokines to combat cancer: the double-edged sword

Abstract

Chemokines are a small group of related chemo-attractant peptides that play an essential role in the homeostatic maintenance of the immune system. They control the recruitment of cells needed for the induction and activation of innate and adaptive immune responses. However, tumors also utilize chemokines to actively progress and evade immunosurveillance. In fact, chemokines are involved directly or indirectly in almost every aspect of tumorigenesis. They mediate survival and metastatic spread of tumors, promote new blood vessel formation (neovascularization) and induce an immunosuppressive microenvironment via recruitment of immunosuppressive cells. As a result, a number of therapeutic strategies have been proposed to target almost every step of the chemokine/chemokine receptor involvement in tumors. Yet, despite occasional success stories, most of them appear to be ineffective or impractical, presumably due to 'nonspecific' harm of cells needed for the elimination of tumor escapees and maintenance of immunological memory. The strategy would only be effective if it also promoted antitumor adaptive immune responses capable of combating a residual disease and tumor relapse.

Figure 1. Chemokines are involved in almost every aspect of tumorigenesis and antitumor immunity

Primary tumors progress producing chemokines (IL-8/CXCL8, MIP-1α/CCL3, TARC/CCL17, MDC/CCL22) that promote neovascularization (1) and escape immunosurveillance via recruitment of immunosuppressive cells, such as T regulatory cells, NK T cells, macrophages and iDC. Tumors metastasize to distant organs, such as skin (2), LN (3), liver (4) and lung, that constitutively produce chemokines (SDF-1/CXCL12, ELC/CCL19 and SLC/CCL21; or TARC/CCL17 and MDC/CCL22). Therefore, to combat the disease and metastatic spread of tumor cells, use of various drugs and specific antibodies that target chemokines or their receptors were proposed, which inhibit neovascularization via expression of angiostatic chemokines (MIG/CXCL9 and IP-10/CXCL10, 9) or depletion of angiogenic chemokines (CXCL8, 9). However, these strategies cannot combat the disease efficiently, particularly relapse, unless they are accompanied with activation of antitumor adaptive immune responses. Immunizations with TAA fused with chemokines (MIP3α-TAA, 5) or with tumor cells modified to express chemokines (MIP-3α/CCL20, IP-10/CXCL10, 6) appear to be potent inducers of antitumor immunity. These vaccines recruit iDCs that take up and present TAAs leading to induction of tumor-specific T-cell responses in secondary lymphoid organs (LN, 3). The activated tumor-specific T cells can efficiently eradicate tumors in the skin (8,2) and other distant sites (7,4). APC: Antigen-presenting cell; DC: Dendritic cell; ELC: EBI1-ligand chemokine; iDC: Immature dendritic cell; IL: Interleukin; IP: Interferon-γ inducible protein; LN: Lymph node; mDC: mature dendritic cellMDC: Monocyte-derived chemokine; MIG: Monokine induged by interferon-γ; MIP: Macrophage inflammatory protein; NK: Natural killer; SDF: Stromal cell-derived factor; SLC: Secondary lymphoid tissue chemokine; TAA: Tumor-associated antigen; TARC: Thymus and activation-regulated chemokine.