Tumor-associated macrophages: function, phenotype, and link to prognosis in human lung cancer.

Macrophages are the dominant leukocyte population found in the tumor microenvironment. Accumulating evidence suggests that these tumor-associated macrophages (TAMs) actively promote all aspects of tumor initiation, growth, and development. However, TAMs are not a single uniform population; instead, they are composed of multiple distinct pro- and anti-tumoral subpopulations with overlapping features depending on a variety of external factors. Defining and differentiating these subsets remains a challenging work-in-progress. These difficulties are apparent in prognostic studies in lung cancer that initially demonstrated conflicting evidence regarding the significance of TAMs but which have more recently clarified and confirmed the clinical importance of these subsets through improved phenotypic capabilities. Thus, these cells represent potential targets for cancer therapeutic initiatives through translational approaches. In this review, we summarize the current understanding of how the tumor microenvironment takes advantage of macrophage plasticity to mold an immunosuppressive population, the phenotypic heterogeneity of TAMs, and their link to prognosis in human lung cancer.

[1]  Shu-Min Lin,et al.  Tumor‐associated macrophages correlate with response to epidermal growth factor receptor‐tyrosine kinase inhibitors in advanced non‐small cell lung cancer , 2012, International journal of cancer.

[2]  D. Gabrilovich,et al.  Coordinated regulation of myeloid cells by tumours , 2012, Nature Reviews Immunology.

[3]  A. Mantovani,et al.  Cancer-related inflammation: common themes and therapeutic opportunities. , 2012, Seminars in cancer biology.

[4]  T. Chatila,et al.  T cell receptor (TCR)-transgenic CD8 lymphocytes rendered insensitive to transforming growth factor beta (TGFβ) signaling mediate superior tumor regression in an animal model of adoptive cell therapy , 2012, Journal of Translational Medicine.

[5]  S. H. van der Burg,et al.  Identification and manipulation of tumor associated macrophages in human cancers , 2011, Journal of Translational Medicine.

[6]  Alexandros Nikolaou,et al.  Mononuclear phagocyte heterogeneity in cancer: different subsets and activation states reaching out at the tumor site. , 2011, Immunobiology.

[7]  Haiquan Chen,et al.  Tumor-associated macrophages provide a suitable microenvironment for non-small lung cancer invasion and progression. , 2011, Lung cancer.

[8]  Juan Gao,et al.  M2-Polarized tumor-associated macrophages are associated with poor prognoses resulting from accelerated lymphangiogenesis in lung adenocarcinoma , 2011, Clinics.

[9]  G. Natoli,et al.  Transcriptional regulation of macrophage polarization: enabling diversity with identity , 2011, Nature Reviews Immunology.

[10]  S. H. van der Burg,et al.  M2 Macrophages Induced by Prostaglandin E2 and IL-6 from Cervical Carcinoma Are Switched to Activated M1 Macrophages by CD4+ Th1 Cells , 2011, The Journal of Immunology.

[11]  S. H. van der Burg,et al.  Activation of Tumor-Promoting Type 2 Macrophages by EGFR-Targeting Antibody Cetuximab , 2011, Clinical Cancer Research.

[12]  Y. Daaka,et al.  Aberrant PGE₂ metabolism in bladder tumor microenvironment promotes immunosuppressive phenotype of tumor-infiltrating myeloid cells. , 2011, International immunopharmacology.

[13]  Mayte Suárez-Fariñas,et al.  Tumor-associated macrophages in the cutaneous SCC microenvironment are heterogeneously activated. , 2011, The Journal of investigative dermatology.

[14]  Haiquan Chen,et al.  Increased IL-10 mRNA expression in tumor-associated macrophage correlated with late stage of lung cancer , 2011, Journal of experimental & clinical cancer research : CR.

[15]  M. Ewen,et al.  CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. , 2011, Cancer cell.

[16]  T. Wynn,et al.  Obstacles and opportunities for understanding macrophage polarization , 2011, Journal of leukocyte biology.

[17]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[18]  F. Heppner,et al.  M2 polarized macrophages and giant cells contribute to myofibrosis in neuromuscular sarcoidosis. , 2011, The American journal of pathology.

[19]  H. Lockstone,et al.  IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses , 2011, Nature Immunology.

[20]  T. Ishikawa,et al.  Prostaglandin E₂ signaling and bacterial infection recruit tumor-promoting macrophages to mouse gastric tumors. , 2011, Gastroenterology.

[21]  J. Vieweg,et al.  Pivotal Advance: Tumor‐mediated induction of myeloid‐derived suppressor cells and M2‐polarized macrophages by altering intracellular PGE2 catabolism in myeloid cells , 2010, Journal of leukocyte biology.

[22]  A. Ochiai,et al.  Stromal Macrophage Expressing CD204 is Associated with Tumor Aggressiveness in Lung Adenocarcinoma , 2010, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[23]  A. Mantovani,et al.  Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm , 2010, Nature Immunology.

[24]  L. Coussens,et al.  Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. , 2010, Cancer research.

[25]  M. Pedriali,et al.  CD8+ T cells expressing IL-10 are associated with a favourable prognosis in lung cancer. , 2010, Lung cancer.

[26]  P. De Baetselier,et al.  Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. , 2010, Cancer research.

[27]  P. Bradding,et al.  Tumour necrosis factor-alpha expression in tumour islets confers a survival advantage in non-small cell lung cancer , 2010, BMC Cancer.

[28]  S. Gordon,et al.  Alternative activation of macrophages: mechanism and functions. , 2010, Immunity.

[29]  Jeffrey W. Pollard,et al.  Macrophage Diversity Enhances Tumor Progression and Metastasis , 2010, Cell.

[30]  Luigi Naldini,et al.  Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors. , 2010, The American journal of pathology.

[31]  Alberto Mantovani,et al.  Macrophages, innate immunity and cancer: balance, tolerance, and diversity. , 2010, Current opinion in immunology.

[32]  Michael C. Ostrowski,et al.  An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. , 2010, Cancer research.

[33]  Lunxu Liu,et al.  The number and microlocalization of tumor-associated immune cells are associated with patient's survival time in non-small cell lung cancer , 2010, BMC Cancer.

[34]  P. Bradding,et al.  Chemokine receptor expression in tumour islets and stroma in non-small cell lung cancer , 2010, BMC Cancer.

[35]  Lunxu Liu,et al.  The M1 form of tumor-associated macrophages in non-small cell lung cancer is positively associated with survival time , 2010, BMC Cancer.

[36]  Jeffrey W Pollard,et al.  Gene Expression Analysis of Macrophages That Facilitate Tumor Invasion Supports a Role for Wnt-Signaling in Mediating Their Activity in Primary Mammary Tumors , 2009, The Journal of Immunology.

[37]  Gisen Kim,et al.  Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis , 2009, Nature Immunology.

[38]  Hua Yu,et al.  STATs in cancer inflammation and immunity: a leading role for STAT3 , 2009, Nature Reviews Cancer.

[39]  N. Mukaida,et al.  Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. , 2009, Cancer research.

[40]  T. Dønnem,et al.  The prognostic value of intraepithelial and stromal innate immune system cells in non‐small cell lung carcinoma , 2009, Histopathology.

[41]  Ruth J. Muschel,et al.  A Distinct Macrophage Population Mediates Metastatic Breast Cancer Cell Extravasation, Establishment and Growth , 2009, PloS one.

[42]  L. Coussens,et al.  CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. , 2009, Cancer cell.

[43]  I. Weissman,et al.  CD47 Is Upregulated on Circulating Hematopoietic Stem Cells and Leukemia Cells to Avoid Phagocytosis , 2009, Cell.

[44]  Jing Xu,et al.  Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1 , 2009, The Journal of experimental medicine.

[45]  P. Allavena,et al.  Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation. , 2009, Human immunology.

[46]  G. Kuttan,et al.  Role of macrophages in tumour progression. , 2009, Immunology letters.

[47]  G. Nuovo,et al.  Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. , 2009, Cancer research.

[48]  P. Bradding,et al.  Macrophages within NSCLC tumour islets are predominantly of a cytotoxic M1 phenotype associated with extended survival , 2009, European Respiratory Journal.

[49]  J. Edwards,et al.  Exploring the full spectrum of macrophage activation , 2008, Nature Reviews Immunology.

[50]  A. Gemma,et al.  Predominant infiltration of macrophages and CD8+ T Cells in cancer nests is a significant predictor of survival in stage IV nonsmall cell lung cancer , 2008, Cancer.

[51]  Mikala Egeblad,et al.  Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy , 2008, Disease Models & Mechanisms.

[52]  Craig Murdoch,et al.  The role of myeloid cells in the promotion of tumour angiogenesis , 2008, Nature Reviews Cancer.

[53]  P. Allavena,et al.  Cancer-related inflammation , 2008, Nature.

[54]  R. Ádány,et al.  Tumor‐infiltrating myeloid‐derived suppressor cells are pleiotropic‐inflamed monocytes/macrophages that bear M1‐ and M2‐type characteristics , 2008, Journal of leukocyte biology.

[55]  Hsuan-Yu Chen,et al.  TREM-1 expression in tumor-associated macrophages and clinical outcome in lung cancer. , 2008, American journal of respiratory and critical care medicine.

[56]  P. Allavena,et al.  The Yin‐Yang of tumor‐associated macrophages in neoplastic progression and immune surveillance , 2008, Immunological reviews.

[57]  Jae Hyun Kim,et al.  High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer , 2008, British Journal of Cancer.

[58]  H. Gascan,et al.  Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. , 2007, Blood.

[59]  M. Pedriali,et al.  Macrophage expression of interleukin-10 is a prognostic factor in nonsmall cell lung cancer , 2007, European Respiratory Journal.

[60]  Jiasen Cheng,et al.  Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. , 2007, Blood.

[61]  C. Lewis,et al.  Inflammation and breast cancer. Microenvironmental factors regulating macrophage function in breast tumours: hypoxia and angiopoietin-2 , 2007, Breast Cancer Research.

[62]  Yarong Wang,et al.  Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. , 2007, Cancer research.

[63]  A. Bikfalvi,et al.  Tumor angiogenesis , 2020, Advances in cancer research.

[64]  J. Pollard,et al.  Macrophages regulate the angiogenic switch in a mouse model of breast cancer. , 2006, Cancer research.

[65]  P. De Baetselier,et al.  Identification of a common gene signature for type II cytokine-associated myeloid cells elicited in vivo in different pathologic conditions. , 2006, Blood.

[66]  S. Rosenberg,et al.  Adoptive immunotherapy for cancer: building on success , 2006, Nature Reviews Immunology.

[67]  Alberto Mantovani,et al.  Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. , 2006, European journal of cancer.

[68]  T. Kawabe,et al.  Expression of macrophage-derived chemokine (MDC)/CCL22 in human lung cancer , 2006, Cancer Immunology, Immunotherapy.

[69]  T. Ottenhoff,et al.  Phenotypic and functional profiling of human proinflammatory type‐1 and anti‐inflammatory type‐2 macrophages in response to microbial antigens and IFN‐γ‐ and CD40L‐mediated costimulation , 2006, Journal of leukocyte biology.

[70]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[71]  T. Waldmann Effective cancer therapy through immunomodulation. , 2006, Annual review of medicine.

[72]  K. O'Byrne,et al.  Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  S. Gordon,et al.  Monocyte and macrophage heterogeneity , 2005, Nature Reviews Immunology.

[74]  B. Dahal,et al.  Macrophage galactose‐type C‐type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation , 2005, Journal of leukocyte biology.

[75]  A. Mantovani,et al.  Smoldering and polarized inflammation in the initiation and promotion of malignant disease. , 2005, Cancer cell.

[76]  Yi-Chen Lin,et al.  Tumor-associated macrophages: the double-edged sword in cancer progression. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[77]  J. Pollard,et al.  A Paracrine Loop between Tumor Cells and Macrophages Is Required for Tumor Cell Migration in Mammary Tumors , 2004, Cancer Research.

[78]  S. Rosenberg,et al.  Cancer immunotherapy: moving beyond current vaccines , 2004, Nature Medicine.

[79]  George Coukos,et al.  Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival , 2004, Nature Medicine.

[80]  J. Brayer,et al.  Arginase I Production in the Tumor Microenvironment by Mature Myeloid Cells Inhibits T-Cell Receptor Expression and Antigen-Specific T-Cell Responses , 2004, Cancer Research.

[81]  F. Balkwill Cancer and the chemokine network , 2004, Nature Reviews Cancer.

[82]  T. Manabe,et al.  Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients , 2004, British Journal of Cancer.

[83]  J. Pollard Tumour-educated macrophages promote tumour progression and metastasis , 2004, Nature Reviews Cancer.

[84]  A. Kargı,et al.  Association of macrophages, mast cells and eosinophil leukocytes with angiogenesis and tumor stage in non-small cell lung carcinomas (NSCLC). , 2004, Lung cancer.

[85]  T. Waldmann,et al.  Immunotherapy: past, present and future , 2003, Nature Medicine.

[86]  Jeremy J. W. Chen,et al.  Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[87]  E. Kay,et al.  Infiltrating immune cells, but not tumour cells, express FasL in non‐small cell lung cancer: No association with prognosis identified in 3‐year follow‐up , 2003, International journal of cancer.

[88]  P. Allavena,et al.  Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. , 2002, Trends in immunology.

[89]  Noam Brown,et al.  The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapies , 2002, The Journal of pathology.

[90]  Andrew V. Nguyen,et al.  Colony-Stimulating Factor 1 Promotes Progression of Mammary Tumors to Malignancy , 2001, The Journal of experimental medicine.

[91]  I. Takanami,et al.  Tumor-Associated Macrophage Infiltration in Pulmonary Adenocarcinoma: Association with Angiogenesis and Poor Prognosis , 1999, Oncology.

[92]  Y. Vodovotz,et al.  Immunocytochemical localization of latent transforming growth factor‐β1 activation by stimulated macrophages , 1999, Journal of cellular physiology.

[93]  A. Harris,et al.  Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. , 1996, Cancer research.

[94]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[95]  I. Fidler,et al.  Recognition and destruction of neoplastic cells by activated macrophages: discrimination of altered self. , 1988, Biochimica et biophysica acta.

[96]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.