Identification and manipulation of tumor associated macrophages in human cancers
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Heusinkveld and van der Burg Journal of Translational Medicine 2011, 9:216 http://www.translational-medicine.com/content/9/1/216 (16 December 2011)
Heusinkveld and van der Burg Journal of Translational Medicine 2011, 9:216 http://www.translational-medicine.com/content/9/1/216
REVIEW
Open Access
Identification and manipulation of tumor associated macrophages in human cancers Moniek Heusinkveld and Sjoerd H van der Burg*
Abstract Evading immune destruction and tumor promoting inflammation are important hallmarks in the development of cancer. Macrophages are present in most human tumors and are often associated with bad prognosis. Tumor associated macrophages come in many functional flavors ranging from what is known as classically activated macrophages (M1) associated with acute inflammation and T-cell immunity to immune suppressive macrophages (M2) associated with the promotion of tumor growth. The role of these functionally different myeloid cells is extensively studied in mice tumor models but dissimilarities in markers and receptors make the direct translation to human cancer difficult. This review focuses on recent reports discriminating the type of infiltrating macrophages in human tumors and the environmental cues present that steer their differentiation. Finally, immunotherapeutic approaches to interfere in this process are discussed. Keywords: Tumor infiltrating macrophages, M1, M2, T cells, immunotherapy
1. Macrophages Macrophages are a heterogeneous population of innate myeloid cells involved in health and disease. Macrophages originate from monocytic precursors in the blood and undergo specific differentiation depending on local cues in the tissue [1]. Roughly two distinct polarization states are recognized; the classically activated type 1 macrophages (M1) and the alternative activated type 2 macrophages (M2). In response to activating danger signals delivered by bacterial products or IFNg, macrophages adapt to a M1 phenotype which is tailormade to attract and activate cells of the adaptive immune system. Important features of M1 macrophages are the expression of iNOS, ROS and the production of NK and type 1 T-cell stimulating cytokine IL-12. M1 macrophages can phagocytose and kill target cells. M2 macrophages can develop in response to for instance IL4 or IL-13[2,3], express abundant scavenger receptors and are associated with high production of IL-10, IL-1b, VEGF and matrix metalloproteinases (MMP). M2 macrophages play a role in parasite clearance and wound healing where they also polarize T cells to Th2 and dampen immune responses [4]. Furthermore * Correspondence: [email protected] Dept. of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands
macrophages are antigen presenting cells (APC) that express class I and class II HLA-molecules and co-stimulatory/inhibitory molecules to instruct T cells, albeit with lesser efficiency than dendritic cells. Notably, the terms M1 and M2 are an oversimplification of the macrophage types that can be detected. Macrophages display grea
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