Tumour-associated macrophages as treatment targets in oncology

Macrophages are crucial drivers of tumour-promoting inflammation. Tumour-associated macrophages (TAMs) contribute to tumour progression at different levels: by promoting genetic instability, nurturing cancer stem cells, supporting metastasis, and taming protective adaptive immunity. TAMs can exert a dual, yin–yang influence on the effectiveness of cytoreductive therapies (chemotherapy and radiotherapy), either antagonizing the antitumour activity of these treatments by orchestrating a tumour-promoting, tissue-repair response or, instead, enhancing the overall antineoplastic effect. TAMs express molecular triggers of checkpoint proteins that regulate T-cell activation, and are targets of certain checkpoint-blockade immunotherapies. Other macrophage-centred approaches to anticancer therapy are under investigation, and include: inhibition of macrophage recruitment to, and/or survival in, tumours; functional re-education of TAMs to an antitumour, 'M1-like' mode; and tumour-targeting monoclonal antibodies that elicit macrophage-mediated extracellular killing, or phagocytosis and intracellular destruction of cancer cells. The evidence supporting these strategies is reviewed herein. We surmise that TAMs can provide tools to tailor the use of cytoreductive therapies and immunotherapy in a personalized medicine approach, and that TAM-focused therapeutic strategies have the potential to complement and synergize with both chemotherapy and immunotherapy.

[1]  Wilfrid Boireau,et al.  Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth , 2012, Nature Medicine.

[2]  M. van de Rijn,et al.  Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor. , 2015, The New England journal of medicine.

[3]  L. Coussens,et al.  Differential macrophage programming in the tumor microenvironment. , 2012, Trends in immunology.

[4]  Y. Saeys,et al.  Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop into Functional Tissue-Resident Macrophages. , 2016, Immunity.

[5]  F. Marincola,et al.  Commensal Bacteria Control Cancer Response to Therapy by Modulating the Tumor Microenvironment , 2013, Science.

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

[7]  S. Groshen,et al.  FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  Juan F. García,et al.  The presence of STAT1-positive tumor-associated macrophages and their relation to outcome in patients with follicular lymphoma. , 2006, Haematologica.

[9]  K. Mertz,et al.  Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis , 2014, Nature.

[10]  K. Garcia,et al.  Durable antitumor responses to CD47 blockade require adaptive immune stimulation , 2016, Proceedings of the National Academy of Sciences.

[11]  Markus G. Manz,et al.  Development of Monocytes, Macrophages, and Dendritic Cells , 2010, Science.

[12]  Eric Vivier,et al.  The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide , 2013, Science.

[13]  J. Tabernero,et al.  Carlumab, an anti-C-C chemokine ligand 2 monoclonal antibody, in combination with four chemotherapy regimens for the treatment of patients with solid tumors: an open-label, multicenter phase 1b study , 2015, Targeted Oncology.

[14]  Matthew J. Craig,et al.  Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. , 2007, Cancer research.

[15]  L. Dwyer-Nield,et al.  Depletion of Tumor-Associated Macrophages Slows the Growth of Chemically Induced Mouse Lung Adenocarcinomas , 2014, Front. Immunol..

[16]  Zhao-You Tang,et al.  High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  C. Lewis,et al.  Macrophage regulation of tumor responses to anticancer therapies. , 2013, Cancer cell.

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

[19]  Ash A. Alizadeh,et al.  Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma , 2010, Cell.

[20]  Peter J. Murray,et al.  Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards , 2016, Nature Communications.

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

[22]  Hideaki Tahara,et al.  Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells , 2011, Proceedings of the National Academy of Sciences.

[23]  R. Wong,et al.  Macrophages mediate gemcitabine resistance of pancreatic adenocarcinoma by upregulating cytidine deaminase , 2014, Oncogene.

[24]  Xuetao Cao,et al.  The origin and function of tumor-associated macrophages , 2014, Cellular and Molecular Immunology.

[25]  G. Mundy Metastasis: Metastasis to bone: causes, consequences and therapeutic opportunities , 2002, Nature Reviews Cancer.

[26]  Zhihong Chen,et al.  Loss of CX3CR1 increases accumulation of inflammatory monocytes and promotes gliomagenesis , 2015, Oncotarget.

[27]  D. Hume,et al.  Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. , 2012, Blood.

[28]  G. Evan,et al.  Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. , 2012, Blood.

[29]  J. Berzofsky,et al.  CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy. , 2014, Cancer research.

[30]  J. Blay,et al.  Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. , 2014, Cancer cell.

[31]  Jens-Peter Volkmer,et al.  Engineered SIRPα Variants as Immunotherapeutic Adjuvants to Anticancer Antibodies , 2013, Science.

[32]  I. Weissman,et al.  Macrophages are critical effectors of antibody therapies for cancer , 2015, mAbs.

[33]  K. Schäkel,et al.  Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy. , 2013, Cancer cell.

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

[35]  N. Gül,et al.  Antibody-Dependent Phagocytosis of Tumor Cells by Macrophages: A Potent Effector Mechanism of Monoclonal Antibody Therapy of Cancer. , 2015, Cancer research.

[36]  L. Zitvogel,et al.  Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1 , 2015, Science.

[37]  Gefeng Zhu,et al.  B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma , 2006, The Journal of experimental medicine.

[38]  C. Glass,et al.  Molecular control of activation and priming in macrophages , 2015, Nature Immunology.

[39]  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.

[40]  M. Mazzone,et al.  Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. , 2013, Cancer cell.

[41]  F. Geissmann,et al.  The development and maintenance of resident macrophages , 2015, Nature Immunology.

[42]  S. Donnini,et al.  Prostaglandin E2 transactivates the colony‐stimulating factor‐1 receptor and synergizes with colony‐stimulating factor‐1 in the induction of macrophage migration via the mitogen‐activated protein kinase ERK1/2 , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[43]  L. Zitvogel,et al.  Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. , 2015, Cancer cell.

[44]  A. Mantovani Reflections on immunological nomenclature: in praise of imperfection , 2016, Nature Immunology.

[45]  Mitsuaki Suzuki,et al.  Upregulation of bikunin in tumor-infiltrating macrophages as a factor of favorable prognosis in ovarian cancer. , 2004, Gynecologic oncology.

[46]  D. Wallwiener,et al.  Reduction in new metastases in breast cancer with adjuvant clodronate treatment. , 1998, The New England journal of medicine.

[47]  A. V. Nguyen,et al.  Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. , 2016, Cancer discovery.

[48]  F. Ginhoux,et al.  Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota , 2015, Science.

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

[50]  R. Jain,et al.  Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages , 2016, Proceedings of the National Academy of Sciences.

[51]  S. Biswas Metabolic Reprogramming of Immune Cells in Cancer Progression. , 2015, Immunity.

[52]  P. Allavena,et al.  Trabectedin, a drug acting on both cancer cells and the tumour microenvironment , 2014, British Journal of Cancer.

[53]  T. Hamilton,et al.  The cell biology of macrophage activation. , 1984, Annual review of immunology.

[54]  D. Metzger,et al.  Patrolling monocytes control tumor metastasis to the lung , 2015, Science.

[55]  R. Evans,et al.  Cooperation of Immune Lymphoid Cells with Macrophages in Tumour Immunity , 1970, Nature.

[56]  S. Schokrpur,et al.  CSF1 receptor targeting in prostate cancer reverses macrophage-mediated resistance to androgen blockade therapy. , 2015, Cancer research.

[57]  Marco Durante,et al.  Immunologically augmented cancer treatment using modern radiotherapy. , 2013, Trends in molecular medicine.

[58]  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.

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

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

[61]  M. Hemann,et al.  Sensitizing Protective Tumor Microenvironments to Antibody-Mediated Therapy , 2014, Cell.

[62]  Ash A. Alizadeh,et al.  CD47 Is an Adverse Prognostic Factor and Therapeutic Antibody Target on Human Acute Myeloid Leukemia Stem Cells , 2009, Cell.

[63]  A. Korman,et al.  Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells , 2013, Cancer Immunology Research.

[64]  Y. Kanai,et al.  Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer , 2013, British Journal of Cancer.

[65]  D. Linehan,et al.  CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. , 2015, Cancer research.

[66]  A. Radomsky,et al.  From the laboratory to the clinic (and back again): How experiments have informed cognitive–behavior therapy for obsessive–compulsive disorder , 2018, Journal of Experimental Psychopathology.

[67]  P. Allavena,et al.  Dual prognostic significance of tumour-associated macrophages in human pancreatic adenocarcinoma treated or untreated with chemotherapy , 2015, Gut.

[68]  M. Hidalgo,et al.  Inhibition of CD47 Effectively Targets Pancreatic Cancer Stem Cells via Dual Mechanisms , 2015, Clinical Cancer Research.

[69]  H. Friess,et al.  Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells , 2013, Hepatology.

[70]  N. Carragher,et al.  FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis , 2015, The Journal of experimental medicine.

[71]  M. Nakagawa,et al.  Prognostic value of tumor‐associated macrophage count in human bladder cancer , 2000, International journal of urology : official journal of the Japanese Urological Association.

[72]  R. Schreiber,et al.  Natural innate and adaptive immunity to cancer. , 2011, Annual review of immunology.

[73]  J. Pollard,et al.  CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages , 2015, Journal of Experimental Medicine.

[74]  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.

[75]  L. Zitvogel,et al.  Autophagy and cellular immune responses. , 2013, Immunity.

[76]  A. Tolcher,et al.  A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors , 2013, Cancer Chemotherapy and Pharmacology.

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

[78]  G. Trinchieri Innate inflammation and cancer: Is it time for cancer prevention? , 2011, F1000 medicine reports.

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

[80]  P. Allavena,et al.  The interaction of anticancer therapies with tumor-associated macrophages , 2015, The Journal of experimental medicine.

[81]  Eric C. Holland,et al.  The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas , 2016, Science.

[82]  P. Carmeliet,et al.  HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. , 2011, Cancer cell.

[83]  S. Demaria,et al.  Systemic effects of local radiotherapy. , 2009, The Lancet. Oncology.

[84]  Helmut Kettenmann,et al.  The role of microglia and macrophages in glioma maintenance and progression , 2015, Nature Neuroscience.

[85]  Drew A. Torigian,et al.  CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans , 2011, Science.

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

[87]  R. Emerson,et al.  PD-1 blockade induces responses by inhibiting adaptive immune resistance , 2014, Nature.

[88]  Yuquan Wei,et al.  Prognostic Significance of Tumor-Associated Macrophages in Solid Tumor: A Meta-Analysis of the Literature , 2012, PloS one.

[89]  S. Akira,et al.  Macrophage/Cancer Cell Interactions Mediate Hormone Resistance by a Nuclear Receptor Derepression Pathway , 2006, Cell.

[90]  A. Mantovani,et al.  Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. , 1996, Blood.

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

[92]  K. Aozasa,et al.  Infiltration of tumour‐associated macrophages in prostate biopsy specimens is predictive of disease progression after hormonal therapy for prostate cancer , 2011, BJU international.

[93]  M. Karjalainen‐Lindsberg,et al.  A High Tumor-Associated Macrophage Content Predicts Favorable Outcome in Follicular Lymphoma Patients Treated with Rituximab and Cyclophosphamide-Doxorubicin-Vincristine-Prednisone , 2007, Clinical Cancer Research.

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

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

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

[97]  Karey Shumansky,et al.  Analysis of multiple biomarkers shows that lymphoma-associated macrophage (LAM) content is an independent predictor of survival in follicular lymphoma (FL). , 2005, Blood.

[98]  R. Advani,et al.  Tumor-associated macrophages predict inferior outcomes in classic Hodgkin lymphoma: a correlative study from the E2496 Intergroup trial. , 2012, Blood.

[99]  N. Hockstein,et al.  CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation. , 2016, Immunity.

[100]  M. Reni,et al.  Basophil Recruitment into Tumor-Draining Lymph Nodes Correlates with Th2 Inflammation and Reduced Survival in Pancreatic Cancer Patients. , 2016, Cancer research.

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

[102]  L. Karin,et al.  炎症依存性ハイリスク神経芽腫サブセットを描写するCOX/mPGES-1/PGE2経路 , 2015 .

[103]  Steven J. M. Jones,et al.  Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. , 2010, The New England journal of medicine.

[104]  R. DuBois,et al.  Eicosanoids and cancer , 2010, Nature Reviews Cancer.

[105]  A. Mantovani,et al.  Rapid killing of actinomycin D-treated tumor cells by human mononuclear cells. I. Effectors belong to the monocyte-macrophage lineage. , 1984, Journal of immunology.

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

[107]  R. Gascoyne,et al.  The Prognostic Impact of CD163-Positive Macrophages in Follicular Lymphoma: A Study from the BC Cancer Agency and the Lymphoma Study Association , 2015, Clinical Cancer Research.

[108]  J. Brown,et al.  Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization. , 2016, Neuro-oncology.

[109]  N. Cook,et al.  Estimates of benefits and harms of prophylactic use of aspirin in the general population , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[110]  P. Dessen,et al.  PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation , 2014, The Journal of experimental medicine.

[111]  L. Esserman,et al.  Proliferating macrophages associated with high grade, hormone receptor negative breast cancer and poor clinical outcome , 2011, Breast Cancer Research and Treatment.

[112]  J. Blay,et al.  CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study. , 2015, The Lancet. Oncology.

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

[114]  Jens-Peter Volkmer,et al.  Anti-CD47 antibody–mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response , 2013, Proceedings of the National Academy of Sciences.

[115]  S. Natsugoe,et al.  Tumor-associated macrophage (TAM) infiltration in gastric cancer. , 2003, Anticancer research.

[116]  G. Zhu,et al.  Cutting Edge: Induction of B7-H4 on APCs through IL-10: Novel Suppressive Mode for Regulatory T Cells1 , 2006, The Journal of Immunology.

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

[118]  Laurence Zitvogel,et al.  Immunogenic cell death in cancer therapy. , 2013, Annual review of immunology.

[119]  K. Movahedi,et al.  The Ontogeny and Microenvironmental Regulation of Tumor-Associated Macrophages. , 2016, Antioxidants & redox signaling.

[120]  B. Faddegon,et al.  TH 2-Polarized CD 4 þ T Cells and Macrophages Limit Ef fi cacy of Radiotherapy , 2015 .

[121]  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.

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

[123]  A. Sica,et al.  M2 Macrophages Phagocytose Rituximab-Opsonized Leukemic Targets More Efficiently than M1 Cells In Vitro1 , 2009, The Journal of Immunology.

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

[125]  T. Graeber,et al.  Inhibition of CSF-1 receptor improves the antitumor efficacy of adoptive cell transfer immunotherapy. , 2014, Cancer research.

[126]  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.

[127]  E. Furth,et al.  Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma , 2015, Cancer Immunology Research.

[128]  R. Palmqvist,et al.  High Macrophage Infiltration along the Tumor Front Correlates with Improved Survival in Colon Cancer , 2007, Clinical Cancer Research.

[129]  S. Singhal,et al.  Monocyte chemoattractant protein-1 blockade inhibits lung cancer tumor growth by altering macrophage phenotype and activating CD8+ cells. , 2011, American journal of respiratory cell and molecular biology.

[130]  Francois Moisan,et al.  Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers , 2014, Molecular oncology.

[131]  Jérôme Galon,et al.  The continuum of cancer immunosurveillance: prognostic, predictive, and mechanistic signatures. , 2013, Immunity.

[132]  P. Allavena,et al.  Functional TRAIL receptors in monocytes and tumor-associated macrophages: A possible targeting pathway in the tumor microenvironment , 2016, Oncotarget.

[133]  P. Sharma,et al.  The future of immune checkpoint therapy , 2015, Science.

[134]  Naveid A Ali,et al.  Real-time intravital imaging establishes tumor-associated macrophages as the extraskeletal target of bisphosphonate action in cancer. , 2015, Cancer discovery.

[135]  A. Ben-Baruch,et al.  The chemokine system, and its CCR5 and CXCR4 receptors, as potential targets for personalized therapy in cancer. , 2014, Cancer letters.

[136]  Eric C. Sorenson,et al.  KIT oncogene inhibition drives intratumoral macrophage M2 polarization , 2013, The Journal of experimental medicine.

[137]  A. Alavi,et al.  A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma , 2013, Clinical Cancer Research.

[138]  A. Mantovani,et al.  A paracrine circuit in the regulation of the proliferation of macrophages infiltrating murine sarcomas. , 1990, Journal of immunology.

[139]  K. Plate,et al.  Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. , 2010, Cancer research.

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

[141]  S. Sozzani,et al.  The CCL3 Family of Chemokines and Innate Immunity Cooperate In Vivo in the Eradication of an Established Lymphoma Xenograft by Rituximab1 , 2007, The Journal of Immunology.

[142]  M. Mazzone,et al.  The impact of hypoxia on tumor-associated macrophages. , 2016, The Journal of clinical investigation.

[143]  M. Rogers,et al.  Bisphosphonates: from the laboratory to the clinic and back again. , 1999, Bone.

[144]  E. Smits,et al.  Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials. , 2016, Pharmacology & therapeutics.

[145]  A. Mantovani,et al.  Phagocytes as Corrupted Policemen in Cancer-Related Inflammation. , 2015, Advances in cancer research.

[146]  D. Peace,et al.  Modulation of monocyte functions by muramyl tripeptide phosphatidylethanolamine in a phase II study in patients with metastatic melanoma. , 1992, Journal of the National Cancer Institute.

[147]  Stephen Mok,et al.  CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. , 2013, Cancer research.

[148]  H. Kohrt,et al.  Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients , 2014, Nature.

[149]  N. Ferrara,et al.  Targeting the tumour vasculature: insights from physiological angiogenesis , 2010, Nature Reviews Cancer.

[150]  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.

[151]  T. Wheeler,et al.  Reduced infiltration of tumor-associated macrophages in human prostate cancer: association with cancer progression. , 2000, Cancer research.

[152]  B. Faddegon,et al.  TH2-Polarized CD4+ T Cells and Macrophages Limit Efficacy of Radiotherapy , 2015, Cancer Immunology Research.

[153]  C. Aspord,et al.  Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation , 2011, The Journal of experimental medicine.

[154]  S. Jalkanen,et al.  Type and location of tumor‐infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients , 2012, International journal of cancer.

[155]  A. Monnier,et al.  Intraperitoneal recombinant interferon gamma in ovarian cancer patients with residual disease at second-look laparotomy. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

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

[158]  P. Allavena,et al.  Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. , 2010, Cancer research.

[159]  Brian Ruffell,et al.  Macrophages and therapeutic resistance in cancer. , 2015, Cancer cell.

[160]  P. Loke,et al.  PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[161]  M. Roussel,et al.  TNF Counterbalances the Emergence of M2 Tumor Macrophages. , 2015, Cell reports.

[162]  Jeffrey W Pollard,et al.  Tumor-associated macrophages: from mechanisms to therapy. , 2014, Immunity.

[163]  M. Prados,et al.  Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. , 2016, Neuro-oncology.

[164]  M. Koch,et al.  Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients. , 2016, Cancer cell.

[165]  Lian Li,et al.  Association of Intra-tumoral Infiltrating Macrophages and Regulatory T Cells Is an Independent Prognostic Factor in Gastric Cancer after Radical Resection , 2011, Annals of Surgical Oncology.

[166]  I. Keklikoglou,et al.  Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy. , 2015, Cancer research.

[167]  Erik Sahai,et al.  Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. , 2005, Cancer research.

[168]  A. Mantovani,et al.  Role of host defense merchanisms in the antitumor activity of adriamycin and daunomycin in mice. , 1979, Journal of the National Cancer Institute.

[169]  K. Odunsi,et al.  PGE2-Driven Induction and Maintenance of Cancer-Associated Myeloid-Derived Suppressor Cells , 2012, Immunological investigations.

[170]  Jing-quan Li,et al.  Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma , 2015, Gut.

[171]  Kathryn J Fowler,et al.  Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. , 2016, The Lancet. Oncology.

[172]  David C. Gondek,et al.  VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses , 2011, The Journal of experimental medicine.

[173]  R. Jordan,et al.  Trastuzumab Triggers Phagocytic Killing of High HER2 Cancer Cells In Vitro and In Vivo by Interaction with Fcγ Receptors on Macrophages , 2015, The Journal of Immunology.

[174]  Young-sil Yoon,et al.  CREB pathway links PGE2 signaling with macrophage polarization , 2015, Proceedings of the National Academy of Sciences.

[175]  A. Mantovani,et al.  Human mature macrophages mediate antibody-dependent cellular cytotoxicity on tumour cells. , 1977, Transplantation.

[176]  K. Pienta,et al.  Phase 2 study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 (CCL2), in metastatic castration-resistant prostate cancer , 2013, Investigational New Drugs.

[177]  D. Felsher,et al.  MYC regulates the antitumor immune response through CD47 and PD-L1 , 2016, Science.

[178]  R. Weissleder,et al.  Immunogenic Chemotherapy Sensitizes Tumors to Checkpoint Blockade Therapy. , 2016, Immunity.

[179]  J. Huh,et al.  CSF-1R expression in tumor-associated macrophages is associated with worse prognosis in classical Hodgkin lymphoma. , 2014, American journal of clinical pathology.

[180]  N. Yamamoto,et al.  Vitamin D3 binding protein (group-specific component) is a precursor for the macrophage-activating signal factor from lysophosphatidylcholine-treated lymphocytes. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[181]  P. Carmeliet,et al.  Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. , 2014, Cancer research.

[182]  C. Garlanda,et al.  Occurrence and significance of tumor‐associated neutrophils in patients with colorectal cancer , 2016, International journal of cancer.

[183]  C. Meyer,et al.  Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients , 2015, Proceedings of the National Academy of Sciences.

[184]  R. Kaur,et al.  Gliomas Promote Immunosuppression through Induction of B7-H1 Expression in Tumor-Associated Macrophages , 2013, Clinical Cancer Research.

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

[186]  G. Kang,et al.  Prognostic Implication of M2 Macrophages Are Determined by the Proportional Balance of Tumor Associated Macrophages and Tumor Infiltrating Lymphocytes in Microsatellite-Unstable Gastric Carcinoma , 2015, PloS one.

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

[188]  A. Mantovani,et al.  Effects on in vitro tumor growth of murine macrophages isolated from sarcoma lines differing in immunogenicity and metastasizing capacity , 1978, International journal of cancer.

[189]  K. Larsson,et al.  COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset , 2015, Proceedings of the National Academy of Sciences.

[190]  T. Matozaki,et al.  The CD47-SIRPα signalling system: its physiological roles and therapeutic application. , 2014, Journal of biochemistry.

[191]  M. Ando,et al.  FcγR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[192]  Xin Lu,et al.  Chemokine (C-C Motif) Ligand 2 Engages CCR2+ Stromal Cells of Monocytic Origin to Promote Breast Cancer Metastasis to Lung and Bone* , 2009, The Journal of Biological Chemistry.

[193]  Will Liao,et al.  The cellular and molecular origin of tumor-associated macrophages , 2014, Science.

[194]  S. Schokrpur,et al.  Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer. , 2015, Cancer research.

[195]  Jennie W. Taylor,et al.  Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival , 2016, Proceedings of the National Academy of Sciences.

[196]  G. Collins The next generation. , 2006, Scientific American.

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

[198]  B. Tomczuk,et al.  JNJ-28312141, a novel orally active colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 receptor tyrosine kinase inhibitor with potential utility in solid tumors, bone metastases, and acute myeloid leukemia , 2009, Molecular Cancer Therapeutics.

[199]  I. Weissman,et al.  Molecular Pathways: Activating T Cells after Cancer Cell Phagocytosis from Blockade of CD47 “Don't Eat Me” Signals , 2015, Clinical Cancer Research.