Macrophages, innate immunity and cancer: balance, tolerance, and diversity.

Smouldering inflammation is a component of the tumor microenvironment and represents the 7(th) hallmark of cancer. Tumor-associated macrophages (TAM) have served as a paradigm for cancer promoting inflammation. Tumor-associated macrophages orchestrate various aspects of cancer, including: diversion and skewing of adaptive responses; cell growth; angiogenesis; matrix deposition and remodelling; the construction of a metastatic niche and actual metastasis; response to hormones and chemotherapeutic agents. T and B cells or cancer cell-derived signals orchestrate the functional reprogramming of TAM. In general TAM acquire M2-like properties and resemble 'tolerant' macrophages, though there is diversity in pathways and phenotypes in different tumors. TAM can also express antitumor activity. Thus, in response to microenvironmental signals, TAM can exert dual influence on tumor growth and progression.

[1]  Katerina Akassoglou,et al.  NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α , 2008, Nature.

[2]  T. Hagemann,et al.  Macrophages Induce Invasiveness of Epithelial Cancer Cells Via NF-κB and JNK1 , 2005, The Journal of Immunology.

[3]  P. Comoglio,et al.  Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages , 2008, The Journal of experimental medicine.

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

[5]  S. Rafii,et al.  VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche , 2005, Nature.

[6]  M. Karin.  Nuclear factor-κB in cancer development and progression , 2006, Nature.

[7]  G. Natoli,et al.  Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB , 2009, Proceedings of the National Academy of Sciences of the United States of America.

[8]  R. Schreiber,et al.  Cancer immunoediting: from immunosurveillance to tumor escape , 2002, Nature Immunology.

[9]  L. Coussens,et al.  De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. , 2005, Cancer cell.

[10]  A. Mantovani,et al.  The origin and function of tumor-associated macrophages. , 1992, Immunology today.

[11]  Gavin P Dunn,et al.  Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. , 2006, Advances in immunology.

[12]  M. Smyth,et al.  A New Therapeutic Target for Leukemia Comes to the Surface , 2009, Cell.

[13]  P. De Baetselier,et al.  Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. , 2008, Blood.

[14]  Wan-Wan Lin,et al.  Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis , 2009, Nature.

[15]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[16]  P. Allavena,et al.  Macrophage polarization in tumour progression. , 2008, Seminars in cancer biology.

[17]  S. Gordon,et al.  Alternative activation of macrophages: an immunologic functional perspective. , 2009, Annual review of immunology.

[18]  John D Lambris,et al.  Is complement good or bad for cancer patients? A new perspective on an old dilemma. , 2009, Trends in immunology.

[19]  P. Allavena,et al.  Pathways connecting inflammation and cancer. , 2008, Current opinion in genetics & development.

[20]  P. Allavena,et al.  The chemokine system in cancer biology and therapy. , 2010, Cytokine & growth factor reviews.

[21]  P. Allavena,et al.  Anti‐tumor and immunomodulatory activity of intraperitoneal IFN‐γ in ovarian carcinoma patients with minimal residual tumor after chemotherapy , 1992, International journal of cancer.

[22]  Matthew J. Craig,et al.  CCL2 and Interleukin-6 Promote Survival of Human CD11b+ Peripheral Blood Mononuclear Cells and Induce M2-type Macrophage Polarization* , 2009, The Journal of Biological Chemistry.

[23]  Hua Yu,et al.  Tumour immunology: Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment , 2007, Nature Reviews Immunology.

[24]  Shizuo Akira,et al.  Signaling to NF-?B by Toll-like receptors , 2007 .

[25]  C. Aspord,et al.  Breast cancer instructs dendritic cells to prime interleukin 13–secreting CD4+ T cells that facilitate tumor development , 2007, The Journal of experimental medicine.

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

[27]  F. Marincola,et al.  Tumour immunity: effector response to tumour and role of the microenvironment , 2008, The Lancet.

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

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

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

[31]  A. Luttun,et al.  Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. , 2010, Blood.

[32]  S. Asgharzadeh,et al.  Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. , 2009, The Journal of clinical investigation.

[33]  A. Feldman,et al.  Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells. , 2009, Blood.

[34]  Shahin Rafii,et al.  Migratory neighbors and distant invaders: tumor-associated niche cells. , 2008, Genes & development.

[35]  A. Mantovani,et al.  The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6 , 2009, Gut.

[36]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[37]  Peter Vaupel,et al.  Hypoxia and aggressive tumor phenotype: implications for therapy and prognosis. , 2008, The oncologist.

[38]  A. Sica,et al.  Altered macrophage differentiation and immune dysfunction in tumor development. , 2007, The Journal of clinical investigation.

[39]  J. Pollard.  Trophic macrophages in development and disease , 2009, Nature Reviews Immunology.

[40]  C. Liu,et al.  Targeting tumor-associated macrophages as a novel strategy against breast cancer. , 2006, The Journal of clinical investigation.

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

[42]  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.

[43]  A. Mantovani,et al.  The chemokine system: redundancy for robust outputs. , 1999, Immunology today.

[44]  A. Mantovani,et al.  Cancer: Inflaming metastasis , 2008, Nature.

[45]  Laurence Zitvogel,et al.  Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy , 2007, Nature Medicine.

[46]  Luigi Naldini,et al.  FcRgamma activation regulates inflammation-associated squamous carcinogenesis. , 2010, Cancer cell.

[47]  M. Hebbar,et al.  Interferon‐γ reverses the immunosuppressive and protumoral properties and prevents the generation of human tumor‐associated macrophages , 2009, International journal of cancer.

[48]  L. Coussens,et al.  Inflammation and cancer , 2002, Nature.

[49]  M. Banerjee,et al.  Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. , 2009, Blood.

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

[51]  J. Talmadge,et al.  Chemokine-mediated rapid turnover of myeloid-derived suppressor cells in tumor-bearing mice. , 2008, Blood.

[52]  T. Hagemann,et al.  The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. , 2007, Cancer research.

[53]  R. Schwendener,et al.  Identification of a subpopulation of macrophages in mammary tumor-bearing mice that are neither M1 nor M2 and are less differentiated. , 2009, Cancer research.

[54]  A. Mantovani,et al.  Regulation of the macrophage content of neoplasms by chemoattractants. , 1983, Science.

[55]  H. Hausmaninger,et al.  Interferon-gamma in the first-line therapy of ovarian cancer: a randomized phase III trial , 2000, British Journal of Cancer.

[56]  A. Sica,et al.  A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). , 2006, Blood.

[57]  T. Lawrence,et al.  “Re-educating” tumor-associated macrophages by targeting NF-κB , 2008, The Journal of experimental medicine.

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

[59]  S. Jalkanen,et al.  Vascular adhesion protein-1 enhances tumor growth by supporting recruitment of Gr-1+CD11b+ myeloid cells into tumors. , 2009, Cancer research.

[60]  J. Tschopp,et al.  Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors , 2009, Nature Medicine.

[61]  J. Pollard,et al.  Microenvironmental regulation of metastasis , 2009, Nature Reviews Cancer.

[62]  Michael L. Wang,et al.  Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. , 2009, Blood.

[63]  J. Erler,et al.  Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. , 2009, Cancer cell.

[64]  S. Gordon,et al.  Ovarian Cancer Cells Polarize Macrophages Toward A Tumor-Associated Phenotype1 , 2006, The Journal of Immunology.

[65]  R. Nibbs,et al.  The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors. , 2007, The Journal of clinical investigation.

[66]  G. Cheng,et al.  Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. , 2009, Cancer cell.

[67]  Y. Ben-Neriah,et al.  Inflammation and cancer: is the link as simple as we think? , 2005, The Journal of investigative dermatology.

[68]  L. Naldini,et al.  Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications. , 2007, Trends in immunology.

[69]  R. Strieter,et al.  NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-gamma and CXCR3 chemokines. , 2009, Blood.

[70]  J. Berek,et al.  Biologic and immunologic therapies for ovarian cancer. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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