Tumour-associated macrophage polarisation and re-education with immunotherapy.

Monocytes/macrophages constitute important contributors of cancer-associated inflammation. Through their plasticity and capacity to become polarised by tumours towards less activatory and more immunosuppressive (M2) phenotypes, tumour-associated macrophages (TAM) are thought to support tumour progression. Orchestrated by T helper 2 (Th2)-biased stimuli, macrophage recruitment, activation and polarisation in tumour microenvironments is associated with poorer clinical outcomes. Their key roles in supporting tumour progression and their capacity for plasticity have focused targeted and immunotherapeutic strategies to counteract macrophage pro-tumourigenic activities and to re-ignite their tumour-cytotoxic power. Therapeutic approaches include blockade of macrophage recruitment into tumours, suppression of TAM survival, re-polarisation towards an M1-like phenotype and antibody therapies to enhance TAM anti-tumoural activities. Future immunotherapeutic directions may include monoclonal antibodies with enhanced effector functions. Antibodies of different classes, including those of the IgE class, shown to restrict tumour growth by harnessing monocyte/macrophage cytotoxic properties in pre-clinical cancer models, may synergise or re-educate these potent immune sentinels to destroy rather than support tumours. Opportunities for monitoring monocyte/macrophage polarisation or activatory signatures in patients may inform clinical management.

[1]  Robert J. Moore,et al.  IgE-antibody-dependent immunotherapy of solid tumors: cytotoxic and phagocytic mechanisms of eradication of ovarian cancer cells. , 2007, Journal of immunology.

[2]  S. Galli,et al.  IgE Enhances Mouse Mast Cell FcεRI Expression In Vitro and In Vivo: Evidence for a Novel Amplification Mechanism in IgE-dependent Reactions , 1997, The Journal of Experimental Medicine.

[3]  Baohui Xu,et al.  Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor β , 2009, Cancer Immunology, Immunotherapy.

[4]  Jacques Ferlay,et al.  The global burden of cancers attributable to infections in the year 2008: a review and synthetic analysis Web appendix section , 2012 .

[5]  A. Mantovani,et al.  TLR activation of tumor‐associated macrophages from ovarian cancer patients triggers cytolytic activity of NK cells , 2014, European journal of immunology.

[6]  G. Steger,et al.  Trastuzumab mediates antibody-dependent cell-mediated cytotoxicity and phagocytosis to the same extent in both adjuvant and metastatic HER2/neu breast cancer patients , 2013, Journal of Translational Medicine.

[7]  A. Sehon,et al.  Growth inhibition of murine mammary carcinoma by monoclonal IgE antibodies specific for the mammary tumor virus , 2005, Cancer Immunology, Immunotherapy.

[8]  A. Mantovani,et al.  Targeting tumor-associated macrophages and inhibition of MCP-1 reduce angiogenesis and tumor growth in a human melanoma xenograft. , 2007, The Journal of investigative dermatology.

[9]  F. Nestle,et al.  Harnessing engineered antibodies of the IgE class to combat malignancy: initial assessment of FcɛRI‐mediated basophil activation by a tumour‐specific IgE antibody to evaluate the risk of type I hypersensitivity , 2011, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[10]  G. Coukos,et al.  Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer , 2009, Journal of Translational Medicine.

[11]  Andrew E. Parker,et al.  Targeting Toll-like receptors: emerging therapeutics? , 2010, Nature Reviews Drug Discovery.

[12]  Christina S. Leslie,et al.  CSF-1R inhibition alters macrophage polarization and blocks glioma progression , 2013, Nature Medicine.

[13]  Yibin Kang,et al.  The metastasis-promoting roles of tumor-associated immune cells , 2013, Journal of Molecular Medicine.

[14]  F. Nestle,et al.  IgE Interacts with Potent Effector Cells Against Tumors: ADCC and ADCP , 2010 .

[15]  David Baltimore,et al.  MicroRNA-155 is induced during the macrophage inflammatory response , 2007, Proceedings of the National Academy of Sciences.

[16]  M. Mareel,et al.  Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y 1086 , c-Src, Erk1/2 and Akt phosphorylation , 2014 .

[17]  M. Herlyn,et al.  Melanoma‐derived conditioned media efficiently induce the differentiation of monocytes to macrophages that display a highly invasive gene signature , 2012, Pigment cell & melanoma research.

[18]  H. Pehamberger,et al.  Active induction of tumor-specific IgE antibodies by oral mimotope vaccination. , 2007, Cancer research.

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

[20]  P. Utz,et al.  Using the allergic immune system to target cancer: activity of IgE antibodies specific for human CD20 and MUC1 , 2012, Cancer Immunology, Immunotherapy.

[21]  Jonathan B. Mitchem,et al.  Inflammatory Monocyte Mobilization Decreases Patient Survival in Pancreatic Cancer: A Role for Targeting the CCL2/CCR2 Axis , 2013, Clinical Cancer Research.

[22]  D. Dombrowicz,et al.  Role of IgE receptors in IgE antibody-dependent cytotoxicity and phagocytosis of ovarian tumor cells by human monocytic cells , 2007, Cancer Immunology, Immunotherapy.

[23]  L. Babiuk,et al.  Immune Mechanisms and Therapeutic Potential of CpG Oligodeoxynucleotides , 2006, International reviews of immunology.

[24]  P. Darcy,et al.  Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy , 2013, Oncoimmunology.

[25]  N. Van Rooijen,et al.  Macrophages and Fc-receptor interactions contribute to the antitumour activities of the anti-CD40 antibody SGN-40 , 2008, British Journal of Cancer.

[26]  M. Kuwano,et al.  Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages , 2008, Cancer science.

[27]  W. Weng,et al.  Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  T. O’Toole,et al.  Myeloid cells as effector cells for monoclonal antibody therapy of cancer. , 2014, Methods.

[29]  D. Quail,et al.  Microenvironmental regulation of tumor progression and metastasis , 2014 .

[30]  M. Dechant,et al.  IgA antibodies for cancer therapy. , 2001, Critical reviews in oncology/hematology.

[31]  E. Stanley,et al.  Growth of Human Mammary Tumor Xenografts in Mice Oligonucleotides and Small Interfering RNAs Suppresses Colony-Stimulating Factor-1 Blockade by Antisense Updated , 2004 .

[32]  R. Xiang,et al.  A Legumain-based minigene vaccine targets the tumor stroma and suppresses breast cancer growth and angiogenesis , 2008, Cancer Immunology, Immunotherapy.

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

[34]  J. Wolchok,et al.  Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti–CTLA-4 therapy against melanoma , 2013, The Journal of experimental medicine.

[35]  M. Willson,et al.  CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans , 2011 .

[36]  A. Krieg,et al.  Therapeutic potential of Toll-like receptor 9 activation , 2006, Nature Reviews Drug Discovery.

[37]  L. Naldini,et al.  A role for miR-155 in enabling tumor-infiltrating innate immune cells to mount effective antitumor responses in mice. , 2013, Blood.

[38]  R. Jordan,et al.  Tumor-Associated Macrophages Promote Invasion while Retaining Fc-Dependent Anti-Tumor Function , 2012, The Journal of Immunology.

[39]  H. Müller-Hermelink,et al.  Lipoptosis: tumor-specific cell death by antibody-induced intracellular lipid accumulation. , 2004, Cancer research.

[40]  Sarah Zohar,et al.  Intracerebral administration of CpG oligonucleotide for patients with recurrent glioblastoma: a phase II study. , 2010, Neuro-oncology.

[41]  T. Daniels,et al.  Characterisation of an engineered trastuzumab IgE antibody and effector cell mechanisms targeting HER2/neu-positive tumour cells , 2009, Cancer Immunology, Immunotherapy.

[42]  S. Karagiannis,et al.  Antibody therapies for melanoma: New and emerging opportunities to activate immunity (Review) , 2014, Oncology reports.

[43]  Zhijin Wu,et al.  Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma , 2008, Molecular Cancer Therapeutics.

[44]  C. Garlanda,et al.  Tumor associated macrophages and neutrophils in tumor progression , 2013, Journal of cellular physiology.

[45]  J. Wigginton,et al.  Anti‐tumour synergy of cytotoxic chemotherapy and anti‐CD40 plus CpG‐ODN immunotherapy through repolarization of tumour‐associated macrophages , 2011, Immunology.

[46]  R. Andreesen,et al.  Adoptive immunotherapy of cancer using monocyte‐derived macrophages: rationale, current status, and perspectives , 1998, Journal of leukocyte biology.

[47]  Leonard G Presta,et al.  Molecular engineering and design of therapeutic antibodies. , 2008, Current opinion in immunology.

[48]  I. Holen,et al.  Tumour macrophages as potential targets of bisphosphonates , 2011, Journal of Translational Medicine.

[49]  K. Kross,et al.  Tumour-associated macrophages secrete IL-6 and MCP-1 in head and neck squamous cell carcinoma tissue , 2007, Acta oto-laryngologica.

[50]  S. Goerdt,et al.  Macrophage activation and polarization: nomenclature and experimental guidelines. , 2014, Immunity.

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

[52]  D. Dombrowicz,et al.  An Antitumor Cellular Vaccine Based on a Mini-Membrane IgE , 2012, Journal of Immunology.

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

[54]  N. Van Rooijen,et al.  Macrophages contribute to the antitumor activity of the anti-CD30 antibody SGN-30. , 2007, Blood.

[55]  Louis M. Weiner,et al.  Antibody-Based Immunotherapy of Cancer , 2012, Cell.

[56]  Jonathan B. Mitchem,et al.  Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. , 2013, Cancer research.

[57]  R. Virchow Cellular pathology as based upon physiological and pathological histology ... / by Rudolf Virchow. Translated from the 2d ed. of the original by Frank Chance. With notes and numerous emendations, principally from MS. notes of the author , 1863 .

[58]  P. Kubes,et al.  Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. , 2014, The Journal of clinical investigation.

[59]  T. Tedder,et al.  Regulatory B cell production of IL-10 inhibits lymphoma depletion during CD20 immunotherapy in mice. , 2011, The Journal of clinical investigation.

[60]  J. Trapani,et al.  Tumor-specific IgE-mediated inhibition of human colorectal carcinoma xenograft growth. , 1998, Oncology research.

[61]  K. Haas,et al.  Lymphoma depletion during CD20 immunotherapy in mice is mediated by macrophage FcgammaRI, FcgammaRIII, and FcgammaRIV. , 2008, Blood.

[62]  E. Stanley,et al.  Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. , 2006, Cancer research.

[63]  C. Garlanda,et al.  Tumor associated macrophages and neutrophils in cancer. , 2013, Immunobiology.

[64]  K. Pienta,et al.  Synergy between anti‐CCL2 and docetaxel as determined by DW‐MRI in a metastatic bone cancer model , 2009, Journal of cellular biochemistry.

[65]  G. Trinchieri,et al.  Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. , 2005, Cancer research.

[66]  Arthur M. Krieg,et al.  Toll-like receptor 9 (TLR9) agonists in the treatment of cancer , 2008, Oncogene.

[67]  U. Bilitewski Determination of immunomodulatory effects: focus on functional analysis of phagocytes as representatives of the innate immune system , 2008, Analytical and bioanalytical chemistry.

[68]  M. Herlyn,et al.  Low-Level Monocyte Chemoattractant Protein-1 Stimulation of Monocytes Leads to Tumor Formation in Nontumorigenic Melanoma Cells1 , 2001, The Journal of Immunology.

[69]  J. Trapani,et al.  The use of chimeric human Fcε receptor I to redirect cytotoxic T lymphocytes to tumors , 1996, Journal of leukocyte biology.

[70]  T. Lawrence,et al.  Inflammation and cancer: a double-edged sword. , 2007, Cancer cell.

[71]  Karin Jirström,et al.  Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. , 2011, Cancer discovery.

[72]  J. Wolchok,et al.  Antibody therapy of cancer , 2012, Nature Reviews Cancer.

[73]  M. Zucchetti,et al.  Role of macrophage targeting in the antitumor activity of trabectedin. , 2013, Cancer cell.

[74]  T. Daniels,et al.  Targeting HER2/neu with a fully human IgE to harness the allergic reaction against cancer cells , 2012, Cancer Immunology, Immunotherapy.

[75]  B. Berwin,et al.  Scavenger receptor-A-targeted leukocyte depletion inhibits peritoneal ovarian tumor progression. , 2007, Cancer research.

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

[77]  Matthew J. Craig,et al.  CCL2 (Monocyte Chemoattractant Protein-1) in cancer bone metastases , 2007, Cancer and Metastasis Reviews.

[78]  M. Pittet,et al.  Therapeutically reeducating macrophages to treat GBM , 2013, Nature Medicine.

[79]  M. Miyazaki,et al.  Stromal MCP‐1 in mammary tumors induces tumor‐associated macrophage infiltration and contributes to tumor progression , 2009, International journal of cancer.

[80]  Brian J. Smith,et al.  Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia , 2012, Leukemia and Lymphoma.

[81]  D. Dombrowicz,et al.  Three-colour flow cytometric method to measure antibody-dependent tumour cell killing by cytotoxicity and phagocytosis. , 2007, Journal of immunological methods.

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

[83]  H. Müller-Hermelink,et al.  Natural IgM antibodies and immunosurveillance mechanisms against epithelial cancer cells in humans. , 2003, Cancer research.

[84]  K. Pienta,et al.  CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis. , 2010, Cytokine & growth factor reviews.

[85]  H. Vollmers,et al.  Natural antibodies and cancer. , 2009, New biotechnology.

[86]  K. Anderson,et al.  Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the Fc{gamma}RIIIa-158 V/V and V/F polymorphism. , 2007, Blood.

[87]  F. Nestle,et al.  Recombinant IgE antibodies for passive immunotherapy of solid tumours: from concept towards clinical application , 2012, Cancer Immunology, Immunotherapy.

[88]  S. Durham,et al.  Activity of human monocytes in IgE antibody‐dependent surveillance and killing of ovarian tumor cells , 2003, European journal of immunology.

[89]  Jinghang Zhang,et al.  CCL2 recruits inflammatory monocytes to facilitate breast tumor metastasis , 2011, Nature.

[90]  F. Nestle,et al.  Diverse matrix metalloproteinase functions regulate cancer amoeboid migration , 2014, Nature Communications.

[91]  J. Spicer,et al.  IgE immunotherapy , 2014, mAbs.

[92]  G. Pawelec,et al.  The nascent field of AllergoOncology , 2012, Cancer Immunology, Immunotherapy.

[93]  A. Bradwell,et al.  Comparative reactivity of human IgE to cynomolgus monkey and human effector cells and effects on IgE effector cell potency , 2014, mAbs.

[94]  Ryan M. O’Connell,et al.  MicroRNA-125b Potentiates Macrophage Activation , 2011, The Journal of Immunology.

[95]  C. Lewis,et al.  NF‐κB as a central regulator of macrophage function in tumors , 2010, Journal of leukocyte biology.

[96]  B. Redman,et al.  Randomized phase 2/3 trial of CpG oligodeoxynucleotide PF‐3512676 alone or with dacarbazine for patients with unresectable stage III and IV melanoma , 2009, Cancer.

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

[98]  S. H. van der Burg,et al.  Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. , 2013, Cancer research.

[99]  A. Mantovani,et al.  Tumor-Associated Macrophages as a Paradigm of Macrophage Plasticity, Diversity, and Polarization: Lessons and Open Questions , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[100]  R. Virchow,et al.  Cellular Pathology, as Based upon Physiological and Pathological Histology , 1860, Nutrition reviews.

[101]  J. Spicer,et al.  Epidemiological associations of allergy, IgE and cancer , 2013, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[102]  R. Schwendener,et al.  Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach , 2006, British Journal of Cancer.

[103]  A. Palucka,et al.  Neutralizing Tumor-Promoting Chronic Inflammation: A Magic Bullet? , 2013, Science.

[104]  F. Nestle,et al.  IgG4 subclass antibodies impair antitumor immunity in melanoma , 2013 .

[105]  A. Riemer,et al.  AllergoOncology: the role of IgE‐mediated allergy in cancer , 2008, Allergy.