ABSTRACT
The immune system can both promote and suppress cancer. Chronic inflammation and proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are considered to be tumour promoting. In contrast, the exact nature of protective antitumour immunity remains obscure. Here, we quantify locally secreted cytokines during primary immune responses against myeloma and B-cell lymphoma in mice. Strikingly, successful cancer immunosurveillance mediated by tumour-specific CD4(+) T cells is consistently associated with elevated local levels of both proinflammatory (IL-1α, IL-1ß and IL-6) and T helper 1 (Th1)-associated cytokines (interferon-γ (IFN-γ), IL-2 and IL-12). Cancer eradication is achieved by a collaboration between tumour-specific Th1 cells and tumour-infiltrating, antigen-presenting macrophages. Th1 cells induce secretion of IL-1ß and IL-6 by macrophages. Th1-derived IFN-γ is shown to render macrophages directly cytotoxic to cancer cells, and to induce macrophages to secrete the angiostatic chemokines CXCL9/MIG and CXCL10/IP-10. Thus, inflammation, when driven by tumour-specific Th1 cells, may prevent rather than promote cancer.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Inflammation/immunology , Lymphoma, B-Cell/immunology , Macrophages/immunology , Multiple Myeloma/immunology , Neoplasms/immunology , Angiostatic Proteins/biosynthesis , Angiostatic Proteins/immunology , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/metabolism , Cell Line, Tumor , Chemokine CXCL10/biosynthesis , Chemokine CXCL10/immunology , Chemokine CXCL9/biosynthesis , Chemokine CXCL9/immunology , Immunohistochemistry , Inflammation/metabolism , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Interleukin-12/biosynthesis , Interleukin-12/immunology , Interleukin-1alpha/biosynthesis , Interleukin-1alpha/immunology , Interleukin-1beta/biosynthesis , Interleukin-1beta/immunology , Interleukin-2/biosynthesis , Interleukin-2/immunology , Interleukin-6/biosynthesis , Interleukin-6/immunology , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/pathology , Macrophages/cytology , Macrophages/metabolism , Mice , Mice, SCID , Multiple Myeloma/metabolism , Multiple Myeloma/pathology , Neoplasms/metabolism , Neoplasms/pathology , Signal Transduction , Th1 Cells/immunology , Th2 Cells/immunology , Tumor MicroenvironmentABSTRACT
Chemokines affect inflammation and cancer through leukocyte attraction and angiogenesis. Here, we demonstrate that CXCL4L1/platelet factor-4 variant (PF-4var), a highly angiostatic chemokine, is poorly chemotactic for phagocytes and is inducible in monocytes by inflammatory mediators but remained undetectable in macrophages and neutrophils. In addition, CXCL4L1/PF-4var production by mesenchymal tumor cells was evidenced in vitro and in vivo by specific ELISA and immunohistochemistry. CXCL4L1/PF-4var, but not CXCL4/PF-4, was coinduced with the angiogenic chemokine CXCL6/granulocyte chemotactic protein-2 (GCP-2) by cytokines, e.g., IL-1beta and IL-17, in sarcoma cells, but not in diploid fibroblasts. Furthermore, the induction of CXCL6/GCP-2 in endothelial cells by IL-1beta was enhanced synergistically by TNF-alpha but inhibited by IFN-gamma, which synergized with IL-1beta to produce the angiostatic CXCL10/IFN-gamma-induced protein-10. These findings indicate that the equilibrium between angiostatic and angiogenic factors during inflammation and tumor progression is rather complex and differs depending on the chemokine, cell type, and stimulus. Selective intervention in the chemokine network may drastically disturb this delicate balance of angiogenesis and tissue repair. Application of angiostatic CXCL4L1/PF-4var without attraction of protumoral phagocytes may be beneficial in cancer therapy.
Subject(s)
Angiogenesis Inducing Agents/antagonists & inhibitors , Angiostatic Proteins/immunology , Chemokine CXCL6/antagonists & inhibitors , Osteosarcoma/pathology , Phagocytes/cytology , Platelet Factor 4/immunology , Antibody Specificity/drug effects , Cell Adhesion/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Chemotactic Factors/pharmacology , Cytokines/pharmacology , Endothelial Cells/cytology , Endothelial Cells/drug effects , Fibroblasts/cytology , Fibroblasts/drug effects , Humans , Immunohistochemistry , Inflammation Mediators , Kinetics , Macrophages/cytology , Macrophages/drug effects , Monocytes/cytology , Monocytes/drug effects , Neovascularization, Physiologic/drug effects , Neutrophils/cytology , Neutrophils/drug effects , Phagocytes/drug effects , Tumor Necrosis Factor-alpha/pharmacologyABSTRACT
Chemokines have pleiotropic effects in regulating immunity, angiogenesis, stem cell trafficking, and mediating organ-specific metastases of cancer. In the context of angiogenesis, the CXC chemokine family is a unique group of cytokines known for their ability to behave in a disparate manner in the regulation of angiogenesis. The glutamic acid-leucine-arginine (ELR+) CXC chemokines are potent promoters of angiogenesis, and mediate their angiogenic activity via signal-coupling of CXCR2 on endothelium. By contrast, members of the CXC chemokine family, such as platelet factor-4 (PF4; CXCL4) and interferon-inducible CXC chemokines are potent inhibitors of angiogenesis, and use CXCR3 on endothelium to mediate their angiostatic activity. This review will discuss the biology of CXC chemokines in the context of angiogenesis related to cancer.
