, Use Imaris Bitplane software for 3D automatic tracking

, Open the 3D image sequence on Imaris. Select "spot" command, and generate manual tracking (mouse click+shift) for all time points for a minimum of 4 different anchor points

, Apply the drift correction using

, Check for the quality of the correction in x, y and particularly in z to avoid artefactual wavering. NOTE: If the correction is not satisfactory

, Cell tracking 1. Use "add new spots" command and select "track spots over time" algorithm setting. Go to next step

, NOTE: The choice will depend on the distinction between objects and specificity of the measured signal. In short, automatic tracking on the whole channel is possible only if detected signal is specific to the object of interest. Because both SHG and ECFP are detected by the NDD after the 485 short pass filter, tracking will be more specific and efficient using the ECFP signal recorded by the NDD after the 500/550 bandpass filters. Clustered or dense packed objects will require manual selection of, Apply automatic cell tracking procedure either on the whole channel of interest using "source channel" command. Set objects (i.e., cells) diameter to 10 µm. Go to next step

, Select "quality" filter type, set the threshold to exclude tracking of unspecific objects. Go to next step

, Brownian Algorithm Motion" with accurate parameters of "Max distance" and "Gap size" between two spots. Validate track generation

, Once tracks are automatically calculated, select "track duration" filter type, set the threshold to eliminate tracks shorter than 120 sec

D. A. Ovchinnikov, Unroll the time bar to check that the objects follow the track paths. If not, use the options of track point correction available in the "edit" tab: Delete false or improper tracks with "delete" command (delete any track point individually using "disconnect" References 1, J Leukoc Biol, vol.83, pp.430-433, 2008.

A. Parihar, T. D. Eubank, and A. I. Doseff, Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death, J Innate Immun, vol.2, pp.204-215, 2010.

F. Geissmann, S. Jung, and D. R. Littman, Blood monocytes consist of two principal subsets with distinct migratory properties, Immunity, vol.19, pp.71-82, 2003.

C. S. Robbins and F. K. Swirski, The multiple roles of monocyte subsets in steady state and inflammation, Cell Mol Life Sci, vol.67, pp.2685-2693, 2010.

C. Shi, Bone marrow mesenchymal stem and progenitor cells induce monocyte emigration in response to circulating toll-like receptor ligands, Immunity, vol.34, pp.590-601, 2011.

S. Jacquelin, CX3CR1 reduces Ly6Chigh-monocyte motility within and release from the bone marrow after chemotherapy in mice, Blood, vol.122, pp.674-683, 2013.

F. K. Swirski, Identification of splenic reservoir monocytes and their deployment to inflammatory sites, Science, vol.325, pp.612-616, 2009.

R. N. Germain, M. J. Miller, M. L. Dustin, and M. C. Nussenzweig, Dynamic imaging of the immune system: progress, pitfalls and promise, Nat Rev Immunol, vol.6, pp.497-507, 2006.

I. F. Charo and R. M. Ransohoff, The many roles of chemokines and chemokine receptors in inflammation, N Engl J Med, vol.354, pp.610-621, 2006.

I. Milo, Dynamic imaging reveals promiscuous crosspresentation of blood-borne antigens to naive CD8+ T cells in the bone marrow, vol.122, pp.193-208, 2013.

L. L. Cavanagh, Activation of bone marrow-resident memory T cells by circulating, antigen-bearing dendritic cells, Nat Immunol, vol.6, pp.1029-1037, 2005.

I. B. Mazo, Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells, Immunity, vol.22, pp.259-270, 2005.

G. S. Travlos, Normal structure, function, and histology of the bone marrow, Toxicol Pathol, vol.34, pp.548-565, 2006.

I. B. Mazo, Hematopoietic progenitor cell rolling in bone marrow microvessels: parallel contributions by endothelial selectins and vascular cell adhesion molecule 1, J Exp Med, vol.188, pp.465-474, 1998.

N. M. Rashidi, In vivo time-lapse imaging of mouse bone marrow reveals differential niche engagement by quiescent and naturally activated hematopoietic stem cells, Blood, 2014.

D. A. Sipkins, In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment, Nature, vol.435, pp.969-973, 2005.

A. Cariappa, Perisinusoidal B cells in the bone marrow participate in T-independent responses to blood-borne microbes, Immunity, vol.23, pp.397-407, 2005.

T. Junt, Dynamic visualization of thrombopoiesis within bone marrow, Science, vol.317, pp.1767-1770, 2007.

C. Auffray, D. Fogg, and M. Garfa, Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior, Science, vol.317, issue.5838, pp.666-670, 2007.
URL : https://hal.archives-ouvertes.fr/pasteur-00337698

S. Yona, K. W. Kim, and Y. Wolf, Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis, Immunity, vol.38, issue.5, pp.79-91, 2013.

C. Sunderköttersunderk¨sunderkötter, T. Nikolic, and M. J. Dillon, Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response, J Immunol, vol.172, issue.7, pp.4410-4417, 2004.

F. K. Swirski, M. Nahrendorf, and M. Etzrodt, tumor-associated cells might allow to further develop and improve anticancer regimen's dosages and combinations, notably those simultaneously targeting the TME. References Afik, J Exp Med, vol.325, issue.5940, pp.2315-2331, 2009.

A. D. Amir-el, K. L. Davis, M. D. Tadmor, E. F. Simonds, J. H. Levine et al., viSNE enables visualization of high dimensional single-cell data and reveals phenotypic heterogeneity of leukemia, Nat Biotechnol, vol.31, pp.545-552, 2013.

B. Barleon, S. Sozzani, D. Zhou, H. A. Weich, A. Mantovani et al., Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1, Blood, vol.87, pp.3336-3343, 1996.

A. Boissonnas, F. Licata, L. Poupel, S. Jacquelin, L. Fetler et al., CD8+ tumor-infiltrating T cells are trapped in the tumor-dendritic cell network, Neoplasia, vol.15, pp.85-94, 2013.
URL : https://hal.archives-ouvertes.fr/hal-01586881

R. L. Bowman, F. Klemm, L. Akkari, S. M. Pyonteck, L. Sevenich et al., Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies, Cell Rep, vol.17, pp.2445-2459, 2016.

M. L. Broz, M. Binnewies, B. Boldajipour, A. E. Nelson, J. L. Pollack et al., Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity, Cancer Cell, vol.26, pp.638-652, 2014.

T. J. Chen and N. Kotecha, Cytobank: providing an analytics platform for community cytometry data analysis and collaboration, Curr Top Microbiol Immunol, vol.377, pp.127-157, 2014.

M. H. Cohen, J. Gootenberg, P. Keegan, P. , and R. , FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer, Oncologist, vol.12, pp.713-718, 2007.

V. Cortez-retamozo, M. Etzrodt, A. Newton, P. J. Rauch, A. Chudnovskiy et al., Origins of tumor-associated macrophages and neutrophils, Proc Natl Acad Sci U S A, vol.109, pp.2491-2496, 2012.

D. Palma, M. , L. , and C. E. , Macrophage regulation of tumor responses to anticancer therapies, Cancer Cell, vol.23, pp.277-286, 2013.

T. A. Doherty, P. Soroosh, N. Khorram, S. Fukuyama, P. Rosenthal et al., The tumor necrosis factor family member LIGHT is a target for asthmatic airway remodeling, Nat Med, vol.17, pp.596-603, 2011.

J. J. Engelhardt, B. Boldajipour, P. Beemiller, P. Pandurangi, C. Sorensen et al., Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells, Cancer Cell, vol.21, pp.402-417, 2012.

R. A. Franklin, W. Liao, A. Sarkar, M. V. Kim, M. R. Bivona et al., The cellular and molecular origin of tumor-associated macrophages, Science, vol.344, pp.921-925, 2014.

L. Galluzzi, A. Buque, O. Kepp, L. Zitvogel, and G. Kroemer, Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents, Cancer Cell, vol.28, pp.690-714, 2015.

L. Gambardella, M. Hemberger, B. Hughes, E. Zudaire, S. Andrews et al., PI3K signaling through the dual GTPase-activating protein ARAP3 is essential for developmental angiogenesis, Sci Signal, vol.3, pp.1327-1340, 2010.

M. Grunewald, I. Avraham, Y. Dor, E. Bachar-lustig, A. Itin et al., VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells, Cell, vol.124, pp.175-189, 2006.

M. Guilliams, I. De-kleer, S. Henri, S. Post, L. Vanhoutte et al., Alveolar macrophages develop from fetal monocytes that differentiate into long-lived cells in the first week of life via GM-CSF, J Exp Med, vol.210, pp.1977-1992, 2013.

P. Hamon, P. L. Loyher, C. Baudesson-de-chanville, F. Licata, C. Combadiere et al., CX3CR1-dependent endothelial margination modulates Ly6Chigh monocyte systemic deployment upon inflammation in mice, 2016.

R. N. Hanna, C. Cekic, D. Sag, R. Tacke, G. D. Thomas et al., Patrolling monocytes control tumor metastasis to the lung, Science, vol.350, pp.985-990, 2015.

M. B. Headley, A. Bins, A. Nip, E. W. Roberts, M. R. Looney et al., , 2016.

, Visualization of immediate immune responses to pioneer metastatic cells in the lung, Nature, vol.531, pp.513-517

R. Hughes, B. Z. Qian, C. Rowan, M. Muthana, I. Keklikoglou et al., Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy, Cancer Res, vol.75, pp.3479-3491, 2015.

S. Jacquelin, F. Licata, K. Dorgham, P. Hermand, L. Poupel et al., CX3CR1 reduces Ly6Chigh-monocyte motility within and release from the bone marrow after chemotherapy in mice, Blood, vol.122, pp.674-683, 2013.

H. Ji, E. Y. Chang, K. Y. Lin, R. J. Kurman, D. M. Pardoll et al., Antigen-specific immunotherapy for murine lung metastatic tumors expressing human papillomavirus type 16 E7 oncoprotein, Int J Cancer, vol.78, pp.41-45, 1998.

S. Jung, J. Aliberti, P. Graemmel, M. J. Sunshine, G. W. Kreutzberg et al., Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion, Mol Cell Biol, vol.20, pp.4106-4114, 2000.

R. N. Kaplan, R. D. Riba, S. Zacharoulis, A. H. Bramley, L. Vincent et al., VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche, Nature, vol.438, pp.820-827, 2005.

T. Kitamura, B. Z. Qian, D. Soong, L. Cassetta, R. Noy et al., CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages, J Exp Med, vol.212, pp.1043-1059, 2015.

Y. Lavin, D. Winter, R. Blecher-gonen, E. David, H. Keren-shaul et al., Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment, Cell, vol.159, pp.1312-1326, 2014.

C. E. Lewis, A. S. Harney, J. W. Pollard, P. L. Loyher, J. Rochefort et al., The Multifaceted Role of Perivascular Macrophages in Tumors, CCR2 Influences T Regulatory Cell Migration to Tumors and Serves as a Biomarker of Cyclophosphamide Sensitivity, vol.30, pp.6483-6494, 2016.

L. Manso, F. Moreno, R. Marquez, B. Castelo, A. Arcediano et al., Use of bevacizumab as a first-line treatment for metastatic breast cancer, Curr Oncol, vol.22, pp.51-60, 2015.

E. Mass, I. Ballesteros, M. Farlik, F. Halbritter, P. Gunther et al., Specification of tissue-resident macrophages during organogenesis, Science, vol.353, 2016.

A. Montero, G. , and S. , Long-Term Complete Remission with nab-Paclitaxel, Bevacizumab, and Gemcitabine Combination Therapy in a Patient with Triple-Negative Metastatic Breast Cancer, Case Rep Oncol, vol.5, pp.687-692, 2012.

A. E. Moran, K. L. Holzapfel, Y. Xing, N. R. Cunningham, J. S. Maltzman et al., T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse, J Exp Med, vol.208, pp.1279-1289, 2011.

G. T. Motz, C. , and G. , The parallel lives of angiogenesis and immunosuppression: cancer and other tales, Nat Rev Immunol, vol.11, pp.702-711, 2011.

D. A. Ovchinnikov, W. J. Van-zuylen, C. E. Debats, K. A. Alexander, S. Kellie et al., Expression of Gal4-dependent transgenes in cells of the mononuclear phagocyte system labeled with enhanced cyan fluorescent protein using Csf1r-Gal4VP16/UAS-ECFP double-transgenic mice, J Leukoc Biol, vol.83, pp.430-433, 2008.

E. G. Perdiguero, K. Klapproth, C. Schulz, K. Busch, M. De-bruijn et al., The Origin of Tissue-Resident Macrophages: When an Erythro-myeloid Progenitor Is an Erythromyeloid Progenitor, Immunity, vol.43, pp.1023-1024, 2015.

J. W. Pollard, Tumour-educated macrophages promote tumour progression and metastasis, Nat Rev Cancer, vol.4, pp.71-78, 2004.

B. Qian, Y. Deng, J. H. Im, R. J. Muschel, Y. Zou et al., A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth, PLoS One, vol.4, pp.39-51, 2009.

B. Z. Qian, H. Zhang, J. Li, T. He, E. J. Yeo et al., FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis, J Exp Med, vol.212, pp.1433-1448, 2015.

M. P. Rodero, L. Poupel, P. L. Loyher, P. Hamon, F. Licata et al., Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells, Cancer Cell, vol.26, pp.623-637, 2014.

K. A. Sauter, C. Pridans, A. Sehgal, C. C. Bain, C. Scott et al., The MacBlue binary transgene (csf1r-gal4VP16/UAS-ECFP) provides a novel marker for visualisation of subsets of monocytes, macrophages and dendritic cells and responsiveness to CSF1 administration, Proc Natl Acad Sci U S A, vol.9, pp.7771-7776, 2014.

L. Tamagnone, Emerging role of semaphorins as major regulatory signals and potential therapeutic targets in cancer, Cancer Cell, vol.22, pp.145-152, 2012.

S. Y. Tan and M. A. Krasnow, Developmental origin of lung macrophage diversity, Development, vol.143, pp.1318-1327, 2016.

E. E. Thornton, M. R. Looney, O. Bose, D. Sen, D. Sheppard et al., Spatiotemporally separated antigen uptake by alveolar dendritic cells and airway presentation to T cells in the lung, J Exp Med, vol.209, pp.1183-1199, 2012.

P. Tymoszuk, H. Evens, V. Marzola, K. Wachowicz, M. H. Wasmer et al., Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, Eur J Immunol, vol.44, pp.1269-1278, 2014.

J. B. Wyckoff, Y. Wang, E. Y. Lin, J. F. Li, S. Goswami et al., Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors, Cancer Res, vol.67, pp.2649-2656, 2007.

D. Abraham, K. Zins, M. Sioud, T. Lucas, R. Schafer et al., Stromal cell-derived CSF-1 blockade prolongs xenograft survival of CSF-1-negative neuroblastoma, Int J Cancer, vol.126, pp.1339-1352, 2010.

C. L. Addison, T. O. Daniel, M. D. Burdick, H. Liu, J. E. Ehlert et al., The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity, J Immunol, vol.165, pp.5269-5277, 2000.

A. Aderem and D. M. Underhill, Mechanisms of phagocytosis in macrophages, Annu Rev Immunol, vol.17, pp.593-623, 1999.

J. A. Aguirre-ghiso, Models, mechanisms and clinical evidence for cancer dormancy, Nat Rev Cancer, vol.7, pp.834-846, 2007.

M. H. Andersen, D. Schrama, P. Thor-straten, and J. C. Becker, Cytotoxic T cells, J Invest Dermatol, vol.126, pp.32-41, 2006.

G. Arango-duque, A. Descoteaux, K. Asano, A. Nabeyama, Y. Miyake et al., CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens, Immunity, vol.34, pp.85-95, 2011.

C. Auffray, D. Fogg, M. Garfa, G. Elain, O. Join-lambert et al., Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior, Science, vol.317, pp.666-670, 2007.
URL : https://hal.archives-ouvertes.fr/pasteur-00337698

C. Auffray, M. H. Sieweke, G. , and F. , Blood monocytes: development, heterogeneity, and relationship with dendritic cells, Annu Rev Immunol, vol.27, pp.669-692, 2009.
URL : https://hal.archives-ouvertes.fr/hal-00407757

S. Augier, T. Ciucci, C. Luci, G. F. Carle, C. Blin-wakkach et al., Inflammatory blood monocytes contribute to tumor development and represent a privileged target to improve host immunosurveillance, J Immunol, vol.185, pp.7165-7173, 2010.

F. Bachelerie, G. J. Graham, M. Locati, A. Mantovani, P. M. Murphy et al., New nomenclature for atypical chemokine receptors, Nat Immunol, vol.15, pp.207-208, 2014.

R. Backer, T. Schwandt, M. Greuter, M. Oosting, F. Jungerkes et al., Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells, Proc Natl Acad Sci U S A, vol.107, pp.216-221, 2010.

C. Bailey, R. Negus, A. Morris, P. Ziprin, R. Goldin et al., Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer, Clin Exp Metastasis, vol.24, pp.121-130, 2007.

F. Balkwill and A. Mantovani, Inflammation and cancer: back to Virchow?, Lancet, vol.357, pp.539-545, 2001.

M. Baratin, L. Simon, A. Jorquera, C. Ghigo, D. Dembele et al., T Cell Zone Resident Macrophages Silently Dispose of Apoptotic Cells in the Lymph Node, Immunity, vol.47, pp.349-362, 2017.
URL : https://hal.archives-ouvertes.fr/hal-01765096

J. F. Bazan, K. B. Bacon, G. Hardiman, W. Wang, K. Soo et al., A new class of membrane-bound chemokine with a CX3C motif, Nature, vol.385, pp.640-644, 1997.

D. Bedoret, H. Wallemacq, T. Marichal, C. Desmet, F. Quesada-calvo et al., Lung interstitial macrophages alter dendritic cell functions to prevent airway allergy in mice, J Clin Invest, vol.119, pp.3723-3738, 2009.

K. U. Belge, F. Dayyani, A. Horelt, M. Siedlar, M. Frankenberger et al., The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF, J Immunol, vol.168, pp.3536-3542, 2002.

S. Z. Ben-sasson, J. Hu-li, J. Quiel, S. Cauchetaux, M. Ratner et al., IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation, Proc Natl Acad Sci U S A, vol.106, pp.7119-7124, 2009.

C. Bogdan, M. Rollinghoff, and A. Diefenbach, Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity, Curr Opin Immunol, vol.12, pp.64-76, 2000.

L. Bonapace, M. M. Coissieux, J. Wyckoff, K. D. Mertz, Z. Varga et al., Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis, Nature, vol.515, pp.130-133, 2014.

L. Boring, J. Gosling, M. Cleary, C. , and I. F. , Decreased lesion formation in CCR2-/-mice reveals a role for chemokines in the initiation of atherosclerosis, Nature, vol.394, pp.894-897, 1998.

L. Borsig, R. Wong, J. Feramisco, D. R. Nadeau, N. M. Varki et al., , 2001.

, Heparin and cancer revisited: mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis, Proc Natl Acad Sci U S A, vol.98, pp.3352-3357

M. C. Bosco, M. Puppo, S. Pastorino, Z. Mi, G. Melillo et al., Hypoxia selectively inhibits monocyte chemoattractant protein-1 production by macrophages, J Immunol, vol.172, pp.1681-1690, 2004.

M. C. Bosco, G. Reffo, M. Puppo, and L. Varesio, Hypoxia inhibits the expression of the CCR5 chemokine receptor in macrophages, Cell Immunol, vol.228, pp.1-7, 2004.

B. Bottazzi, S. Walter, D. Govoni, F. Colotta, and A. Mantovani, Monocyte chemotactic cytokine gene transfer modulates macrophage infiltration, growth, and susceptibility to IL-2 therapy of a murine melanoma, J Immunol, vol.148, pp.1280-1285, 1992.

V. Bronte and P. Zanovello, Regulation of immune responses by L-arginine metabolism, Nat Rev Immunol, vol.5, pp.641-654, 2005.

M. Burnet, Cancer; a biological approach. I. The processes of control, Br Med J, vol.1, pp.779-786, 1957.

J. J. Campbell, G. Haraldsen, J. Pan, J. Rottman, S. Qin et al., The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells, Nature, vol.400, pp.776-780, 1999.

L. M. Carlin, E. G. Stamatiades, C. Auffray, R. N. Hanna, L. Glover et al., Nr4a1-dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate their disposal, Cell, vol.153, pp.362-375, 2013.

C. V. Carman, Mechanisms for transcellular diapedesis: probing and pathfinding by 'invadosome-like protrusions, J Cell Sci, vol.122, pp.3025-3035, 2009.

T. Celia-terrassa and Y. Kang, Distinctive properties of metastasis-initiating cells, Genes Dev, vol.30, pp.892-908, 2016.

C. L. Chaffer and R. A. Weinberg, A perspective on cancer cell metastasis, Science, vol.331, pp.1559-1564, 2011.

M. P. Chao, I. L. Weissman, and R. Majeti, The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications, Curr Opin Immunol, vol.24, pp.225-232, 2012.

I. F. Charo and R. M. Ransohoff, The many roles of chemokines and chemokine receptors in inflammation, N Engl J Med, vol.354, pp.610-621, 2006.

M. A. Cheever, J. P. Allison, A. S. Ferris, O. J. Finn, B. M. Hastings et al., The prioritization of cancer antigens: a national cancer institute pilot project for the acceleration of translational research, Clin Cancer Res, vol.15, pp.5323-5337, 2009.

C. Cheong, I. Matos, J. H. Choi, D. B. Dandamudi, E. Shrestha et al., Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas, Cell, vol.143, pp.416-429, 2010.

C. S. Chiang, S. Y. Fu, S. C. Wang, C. F. Yu, F. H. Chen et al., FDA drug approval summary: bevacizumab (Avastin) plus Carboplatin and Paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer, Front Oncol, vol.2, pp.713-718, 2007.

F. Colotta, P. Allavena, A. Sica, C. Garlanda, and A. Mantovani, Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability, Carcinogenesis, vol.30, pp.1073-1081, 2009.

J. Condeelis and J. W. Pollard, Macrophages: obligate partners for tumor cell migration, invasion, and metastasis, Cell, vol.124, pp.263-266, 2006.

K. A. Connolly, B. A. Belt, N. M. Figueroa, A. Murthy, A. Patel et al., Increasing the efficacy of radiotherapy by modulating the CCR2/CCR5 chemokine axes, Oncotarget, vol.7, pp.86522-86535, 2016.

R. I. Connor, L. Shen, and M. W. Fanger, Evaluation of the antibody-dependent cytotoxic capabilities of individual human monocytes. Role of Fc gamma RI and Fc gamma RII and the effects of cytokines at the single cell level, J Immunol, vol.145, pp.1483-1489, 1990.

C. Debru, A particular form of chemotaxis: necrotaxis. An historical view, Blood Cells, vol.19, pp.20-33, 1993.

J. C. Deng and T. J. Standiford, Growth factors and cytokines in acute lung injury, 2011.

, Compr Physiol, vol.1, pp.81-104

L. Deng, J. F. Zhou, R. S. Sellers, J. F. Li, A. V. Nguyen et al., A novel mouse model of inflammatory bowel disease links mammalian target of rapamycin-dependent hyperproliferation of colonic epithelium to inflammation-associated tumorigenesis, Am J Pathol, vol.176, pp.952-967, 2010.

R. M. Devalaraja, L. B. Nanney, J. Du, Q. Qian, Y. Yu et al., Delayed wound healing in CXCR2 knockout mice, J Invest Dermatol, vol.115, pp.234-244, 2000.

A. Didierlaurent, M. Simonet, and J. C. Sirard, Innate and acquired plasticity of the intestinal immune system, Cell Mol Life Sci, vol.62, pp.1285-1287, 2005.
URL : https://hal.archives-ouvertes.fr/inserm-00000044

J. A. Divietro, M. J. Smith, B. R. Smith, L. Petruzzelli, R. S. Larson et al., Immobilized IL-8 triggers progressive activation of neutrophils rolling in vitro on Pselectin and intercellular adhesion molecule-1, J Immunol, vol.167, pp.4017-4025, 2001.

M. Doitsidou, M. Reichman-fried, J. Stebler, M. Koprunner, J. Dorries et al., Guidance of primordial germ cell migration by the chemokine SDF-1, Cell, vol.111, pp.647-659, 2002.

H. F. Dvorak, Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing, N Engl J Med, vol.315, pp.1650-1659, 1986.

M. Erreni, G. Solinas, P. Brescia, D. Osti, F. Zunino et al., Human glioblastoma tumours and neural cancer stem cells express the chemokine CX3CL1 and its receptor CX3CR1, Eur J Cancer, vol.46, pp.3383-3392, 2010.

B. T. Fife, G. B. Huffnagle, W. A. Kuziel, and W. J. Karpus, CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis, J Exp Med, vol.192, pp.899-905, 2000.

A. Flores-langarica, J. L. Marshall, S. Bobat, E. Mohr, J. Hitchcock et al., T-zone localized monocyte-derived dendritic cells promote Th1 priming to Salmonella, Eur J Immunol, vol.41, pp.2654-2665, 2011.

A. M. Fong, L. A. Robinson, D. A. Steeber, T. F. Tedder, O. Yoshie et al., Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow, J Exp Med, vol.188, pp.1413-1419, 1998.

R. A. Franklin, W. Liao, A. Sarkar, M. V. Kim, M. R. Bivona et al., The cellular and molecular origin of tumor-associated macrophages, Science, vol.344, pp.921-925, 2014.

J. Galon, A. Costes, F. Sanchez-cabo, A. Kirilovsky, B. Mlecnik et al., Type, density, and location of immune cells within human colorectal tumors predict clinical outcome, Science, vol.313, pp.1960-1964, 2006.

J. Gamrekelashvili, R. Giagnorio, J. Jussofie, O. Soehnlein, J. Duchene et al., Regulation of monocyte cell fate by blood vessels mediated by Notch signalling, Vet Immunol Immunopathol, vol.7, pp.127-136, 2002.

K. J. Garton, P. J. Gough, C. P. Blobel, G. Murphy, D. R. Greaves et al., Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1), J Biol Chem, vol.276, pp.37993-38001, 2001.

F. Geissmann, S. Jung, and D. R. Littman, Blood monocytes consist of two principal subsets with distinct migratory properties, Immunity, vol.19, pp.71-82, 2003.

F. Geissmann, M. G. Manz, S. Jung, M. H. Sieweke, M. Merad et al., , 2010.

, Development of monocytes, macrophages, and dendritic cells, Science, vol.327, pp.656-661

R. E. Gerszten, E. A. Garcia-zepeda, Y. C. Lim, M. Yoshida, H. A. Ding et al., MCP-1 and IL-8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions, Nature, vol.398, pp.718-723, 1999.

S. L. Gibbings, S. M. Thomas, S. M. Atif, A. L. Mccubbrey, A. N. Desch et al., Three Unique Interstitial Macrophages in the Murine Lung at Steady State, Am J Respir Cell Mol Biol, vol.57, pp.66-76, 2017.

J. Gilbert, J. Lekstrom-himes, D. Donaldson, Y. Lee, M. Hu et al., Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region, Am J Cardiol, vol.107, pp.906-911, 2011.

F. Ginhoux, M. Greter, M. Leboeuf, S. Nandi, P. See et al., Fate mapping analysis reveals that adult microglia derive from primitive macrophages, Science, vol.330, pp.841-845, 2010.

F. Ginhoux, G. , and M. , Tissue-Resident Macrophage Ontogeny and Homeostasis, Immunity, vol.44, pp.439-449, 2016.

F. Ginhoux, J. , and S. , Monocytes and macrophages: developmental pathways and tissue homeostasis, Nat Rev Immunol, vol.14, pp.392-404, 2014.

W. G. Glass, J. K. Lim, R. Cholera, A. G. Pletnev, J. L. Gao et al., , 2005.

, Chemokine receptor CCR5 promotes leukocyte trafficking to the brain and survival in West Nile virus infection, J Exp Med, vol.202, pp.1087-1098

V. Goede, L. Brogelli, M. Ziche, A. , and H. G. , Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1, Int J Cancer, vol.82, pp.765-770, 1999.

J. W. Goodman, On the Origin of Peritoneal Fluid Cells, Blood, vol.23, pp.18-26, 1964.

S. Gordon, Alternative activation of macrophages, Nat Rev Immunol, vol.3, pp.23-35, 2003.
URL : https://hal.archives-ouvertes.fr/hal-00474829

G. J. Graham, E. G. Wright, R. Hewick, S. D. Wolpe, N. M. Wilkie et al., Identification and characterization of an inhibitor of haemopoietic stem cell proliferation, Nature, vol.344, pp.442-444, 1990.

G. K. Griffin, G. Newton, M. L. Tarrio, D. X. Bu, E. Maganto-garcia et al., IL-17 and TNF-alpha sustain neutrophil recruitment during inflammation through synergistic effects on endothelial activation, J Immunol, vol.188, pp.6287-6299, 2012.

S. I. Grivennikov, F. R. Greten, K. , and M. , Immunity, inflammation, and cancer. Cell, vol.140, pp.883-899, 2010.

L. Gu, S. Tseng, R. M. Horner, C. Tam, M. Loda et al., Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1, Nature, vol.404, pp.407-411, 2000.

M. Guilliams, F. Ginhoux, C. Jakubzick, S. H. Naik, N. Onai et al., Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny, Nat Rev Immunol, vol.14, pp.571-578, 2014.

G. P. Gupta, M. , and J. , Cancer metastasis: building a framework, Cell, vol.127, pp.679-695, 2006.

D. Hackel, D. Pflucke, A. Neumann, J. Viebahn, S. Mousa et al., The connection of monocytes and reactive oxygen species in pain, PLoS One, vol.8, p.63564, 2013.

S. Haeberlein, H. Sebald, C. Bogdan, and U. Schleicher, IL-18, but not IL-15, contributes to the IL-12-dependent induction of NK-cell effector functions by Leishmania infantum in vivo, Eur J Immunol, vol.40, pp.1708-1717, 2010.

R. N. Hanna, L. M. Carlin, H. G. Hubbeling, D. Nackiewicz, A. M. Green et al., The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C-monocytes, Nat Immunol, vol.12, pp.778-785, 2011.

R. N. Hanna, C. Cekic, D. Sag, R. Tacke, G. D. Thomas et al., Patrolling monocytes control tumor metastasis to the lung, Science, vol.350, pp.985-990, 2015.

S. Hardtke, L. Ohl, and R. Forster, Balanced expression of CXCR5 and CCR7 on follicular T helper cells determines their transient positioning to lymph node follicles and is essential for efficient B-cell help, Blood, vol.106, pp.1924-1931, 2005.

D. Hashimoto, A. Chow, C. Noizat, P. Teo, M. B. Beasley et al., Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes, Immunity, vol.38, pp.792-804, 2013.

L. Hefler, C. Tempfer, G. Heinze, K. Mayerhofer, G. Breitenecker et al., Monocyte chemoattractant protein-1 serum levels in ovarian cancer patients, Br J Cancer, vol.81, pp.855-859, 1999.

K. Y. Helmy, K. J. Katschke, . Jr, N. N. Gorgani, N. M. Kljavin et al., CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens, Cell, vol.124, pp.915-927, 2006.

L. Hernandez, T. Smirnova, D. Kedrin, J. Wyckoff, L. Zhu et al., The EGF/CSF-1 paracrine invasion loop can be triggered by heregulin beta1 and CXCL12, Cancer Res, vol.69, pp.3221-3227, 2009.

S. Herter, M. C. Birk, C. Klein, C. Gerdes, P. Umana et al., , 2014.

, Glycoengineering of therapeutic antibodies enhances monocyte/macrophage-mediated phagocytosis and cytotoxicity, J Immunol, vol.192, pp.2252-2260

M. Heusinkveld, P. J. De-vos-van-steenwijk, R. Goedemans, T. H. Ramwadhdoebe, A. Gorter et al., M2 macrophages induced by prostaglandin E2 and IL-6 from cervical carcinoma are switched to activated M1 macrophages by CD4+ Th1 cells, J Immunol, vol.187, pp.1157-1165, 2011.

A. Hochreiter-hufford, K. S. Ravichandran, G. Hoeffel, J. Chen, Y. Lavin et al., C-Myb(+) erythro-myeloid progenitor-derived fetal monocytes give rise to adult tissue-resident macrophages, Cold Spring Harb Perspect Biol, vol.5, pp.665-678, 2013.

R. Hughes, B. Z. Qian, C. Rowan, M. Muthana, I. Keklikoglou et al., Perivascular M2 Macrophages Stimulate Tumor Relapse after Chemotherapy, Cancer Res, vol.75, pp.3479-3491, 2015.

C. Hundhausen, D. Misztela, T. A. Berkhout, N. Broadway, P. Saftig et al., The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion, Blood, vol.102, pp.1186-1195, 2003.

S. M. Hurst, T. S. Wilkinson, R. M. Mcloughlin, S. Jones, S. Horiuchi et al., , vol.14, pp.705-714, 2001.

M. L. Huynh, V. A. Fadok, and P. M. Henson, Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation, J Clin Invest, vol.109, pp.41-50, 2002.

M. Iga, A. Boissonnas, B. Mahe, O. Bonduelle, C. Combadiere et al., Single CX3CL1-Ig DNA administration enhances T cell priming in vivo, Vaccine, vol.25, pp.4554-4563, 2007.

T. Imaizumi, H. Yoshida, and K. Satoh, Regulation of CX3CL1/fractalkine expression in endothelial cells, J Atheroscler Thromb, vol.11, pp.15-21, 2004.

B. C. Isenberg, P. A. Dimilla, M. Walker, S. Kim, and J. Y. Wong, Vascular smooth muscle cell durotaxis depends on substrate stiffness gradient strength, Biophys J, vol.97, pp.1313-1322, 2009.

S. Jacquelin, F. Licata, K. Dorgham, P. Hermand, L. Poupel et al., CX3CR1 reduces Ly6Chighmonocyte motility within and release from the bone marrow after chemotherapy in mice, Blood, vol.122, pp.674-683, 2013.

C. Jakubzick, E. L. Gautier, S. L. Gibbings, D. K. Sojka, A. Schlitzer et al., Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes, Immunity, vol.39, pp.599-610, 2013.

C. H. Jenh, M. A. Cox, L. Cui, E. P. Reich, L. Sullivan et al., A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection, Proc Natl Acad Sci U S A, vol.13, pp.12425-12430, 2011.

B. Johnston and E. C. Butcher, Chemokines in rapid leukocyte adhesion triggering and migration, Semin Immunol, vol.14, pp.83-92, 2002.

B. A. Jones, M. Beamer, A. , and S. , Fractalkine/CX3CL1: a potential new target for inflammatory diseases, Mol Interv, vol.10, pp.263-270, 2010.

K. Jung, T. Heishi, O. F. Khan, P. S. Kowalski, J. Incio et al., Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy, J Clin Invest, vol.127, pp.3039-3051, 2017.

Y. Kakuta, M. Okumi, S. Miyagawa, K. Tsutahara, T. Abe et al., Blocking of CCR5 and CXCR3 suppresses the infiltration of macrophages in acute renal allograft rejection, Transplantation, vol.93, pp.24-31, 2012.

M. Kaur and D. Singh, Neutrophil chemotaxis caused by chronic obstructive pulmonary disease alveolar macrophages: the role of CXCL8 and the receptors CXCR1/CXCR2, J Pharmacol Exp Ther, vol.347, pp.173-180, 2013.

G. S. Kelner, J. Kennedy, K. B. Bacon, S. Kleyensteuber, D. A. Largaespada et al., Lymphotactin: a cytokine that represents a new class of chemokine, Science, vol.266, pp.1395-1399, 1994.

H. T. Khong and N. P. Restifo, Natural selection of tumor variants in the generation of "tumor escape" phenotypes, Nat Immunol, vol.3, pp.999-1005, 2002.

R. Kim, M. Emi, T. , and K. , Cancer immunoediting from immune surveillance to immune escape, Immunology, vol.121, pp.1-14, 2007.

T. S. Kim and T. J. Braciale, Respiratory dendritic cell subsets differ in their capacity to support the induction of virus-specific cytotoxic CD8+ T cell responses, Nat Immun Cell Growth Regul, vol.4, pp.161-166, 1987.

H. J. Ko, J. L. Brady, V. Ryg-cornejo, D. S. Hansen, D. Vremec et al., GM-CSF-responsive monocyte-derived dendritic cells are pivotal in Th17 pathogenesis, J Immunol, vol.192, pp.2202-2209, 2014.

C. M. Koebel, W. Vermi, J. B. Swann, N. Zerafa, S. J. Rodig et al., Adaptive immunity maintains occult cancer in an equilibrium state, Nature, vol.450, pp.903-907, 2007.

T. P. Koestler, W. J. Johnson, D. Rieman, B. J. Dalton, R. G. Greig et al., Differential expression of murine macrophage-mediated tumor cytotoxicity induced by interferons, Cancer Res, vol.47, pp.2804-2808, 1987.

M. Kohyama, W. Ise, B. T. Edelson, P. R. Wilker, K. Hildner et al., Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis, Nature, vol.457, pp.318-321, 2009.

M. D. Krathwohl and J. L. Kaiser, Chemokines promote quiescence and survival of human neural progenitor cells, Stem Cells, vol.22, pp.109-118, 2004.

P. Krause, V. Morris, J. A. Greenbaum, Y. Park, U. Bjoerheden et al., IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis, IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses, vol.6, pp.231-238, 2011.

S. R. Krutzik, B. Tan, H. Li, M. T. Ochoa, P. T. Liu et al., TLR activation triggers the rapid differentiation of monocytes into macrophages and dendritic cells, Nat Med, vol.11, pp.653-660, 2005.

I. Kryczek, L. Zou, P. Rodriguez, G. Zhu, S. Wei et al., B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma, J Exp Med, vol.203, pp.871-881, 2006.

D. M. Kuang, Q. Zhao, C. Peng, J. Xu, J. P. Zhang et al., , 2009.

, Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1, J Exp Med, vol.206, pp.1327-1337

L. Landsman, L. Bar-on, A. Zernecke, K. W. Kim, R. Krauthgamer et al., CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival, Blood, vol.113, pp.963-972, 2009.

L. Lasagni, M. Francalanci, F. Annunziato, E. Lazzeri, S. Giannini et al., An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4, J Exp Med, vol.197, pp.1537-1549, 2003.

E. Lavergne, B. Combadiere, O. Bonduelle, M. Iga, J. L. Gao et al., Fractalkine mediates natural killerdependent antitumor responses in vivo, Cancer Res, vol.63, pp.7468-7474, 2003.

Y. Lavin, M. , and M. , Macrophages: gatekeepers of tissue integrity, Cancer Immunol Res, vol.1, pp.201-209, 2013.

T. Leber, The BOWMAN LECTURE on the PRESENT POSITION of OUR KNOWLEDGE of INFLAMMATION with ESPECIAL REFERENCE to INFLAMMATION of the EYE: Delivered before the Ophthalmological Society of the United Kingdom, Br Med J, vol.1, pp.1357-1358, 1892.

H. W. Lee, H. J. Choi, S. J. Ha, K. T. Lee, and Y. G. Kwon, Recruitment of monocytes/macrophages in different tumor microenvironments, Biochim Biophys Acta, vol.1835, pp.170-179, 2013.

R. D. Leek, H. , and A. L. , Tumor-associated macrophages in breast cancer, J Mammary Gland Biol Neoplasia, vol.7, pp.177-189, 2002.

B. Leon, A. , and C. , Monocyte migration to inflamed skin and lymph nodes is differentially controlled by L-selectin and PSGL-1, Blood, vol.111, pp.3126-3130, 2008.

B. Leon, M. Lopez-bravo, A. , and C. , Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania, Immunity, vol.26, pp.519-531, 2007.

C. Lewis, M. , and C. , Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies, Am J Pathol, vol.167, pp.627-635, 2005.

C. E. Lewis, A. S. Harney, and J. W. Pollard, The Multifaceted Role of Perivascular Macrophages in Tumors, Cancer Cell, vol.30, p.365, 2016.

C. Li, B. Liu, Z. Dai, and Y. Tao, Knockdown of VEGF receptor-1 (VEGFR-1) impairs macrophage infiltration, angiogenesis and growth of clear cell renal cell carcinoma (CRCC), Cancer Biol Ther, vol.12, pp.872-880, 2011.

S. Y. Lim, A. E. Yuzhalin, A. N. Gordon-weeks, and R. J. Muschel, Targeting the CCL2-CCR2 signaling axis in cancer metastasis, Oncotarget, vol.7, pp.28697-28710, 2016.

E. Y. Lin, A. V. Nguyen, R. G. Russell, and J. W. Pollard, Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy, J Exp Med, vol.193, pp.727-740, 2001.

E. Y. Lin and J. W. Pollard, Macrophages: modulators of breast cancer progression, Novartis Found Symp, vol.256, pp.259-169, 2004.

P. Loetscher, C. , and I. , Agonistic and antagonistic activities of chemokines, J Leukoc Biol, vol.69, pp.881-884, 2001.

P. L. Loyher, J. Rochefort, C. Baudesson-de-chanville, P. Hamon, G. Lescaille et al., , p.2, 2016.

, Influences T Regulatory Cell Migration to Tumors and Serves as a Biomarker of Cyclophosphamide Sensitivity, Cancer Res, vol.76, pp.6483-6494

S. A. Luther and J. G. Cyster, Chemokines as regulators of T cell differentiation, Nat Immunol, vol.2, pp.102-107, 2001.

Y. Ma, S. Adjemian, S. R. Mattarollo, T. Yamazaki, L. Aymeric et al., Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells, Immunity, vol.38, pp.729-741, 2013.
URL : https://hal.archives-ouvertes.fr/hal-02047416

S. Mahalingam and G. Karupiah, Chemokines and chemokine receptors in infectious diseases, Immunol Cell Biol, vol.77, pp.469-475, 1999.

N. Makita, Y. Hizukuri, K. Yamashiro, M. Murakawa, and Y. Hayashi, IL-10 enhances the phenotype of M2 macrophages induced by IL-4 and confers the ability to increase eosinophil migration, Int Immunol, vol.27, pp.131-141, 2015.

A. Mantovani, The chemokine system: redundancy for robust outputs, Immunol Today, vol.20, pp.254-257, 1999.

A. Mantovani, F. Marchesi, A. Malesci, L. Laghi, A. et al., Tumourassociated macrophages as treatment targets in oncology, Nat Rev Clin Oncol, vol.14, pp.399-416, 2017.

A. Mantovani and A. Sica, Macrophages, innate immunity and cancer: balance, tolerance, and diversity, Curr Opin Immunol, vol.22, pp.231-237, 2010.

A. Mantovani, A. Sica, S. Sozzani, P. Allavena, A. Vecchi et al., The chemokine system in diverse forms of macrophage activation and polarization, Trends Immunol, vol.25, pp.677-686, 2004.

L. Martinez-lostao, A. Anel, and J. Pardo, How Do Cytotoxic Lymphocytes Kill Cancer Cells?, Clin Cancer Res, vol.21, pp.5047-5056, 2015.

L. Martinez-pomares, G. , and S. , CD169+ macrophages at the crossroads of antigen presentation, Trends Immunol, vol.33, pp.66-70, 2012.

F. O. Martinez, G. , S. Mass, E. Ballesteros, I. Farlik et al., The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6, 13, 2014.

K. Matsushima, C. G. Larsen, G. C. Dubois, and J. J. Oppenheim, Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line, J Exp Med, vol.169, pp.1485-1490, 1989.

H. M. Mcgettrick, J. M. Lord, K. Q. Wang, G. E. Rainger, C. D. Buckley et al., Chemokine-and adhesion-dependent survival of neutrophils after transmigration through cytokine-stimulated endothelium, J Leukoc Biol, vol.79, pp.779-788, 2006.

O. Medina-contreras, D. Geem, O. Laur, I. R. Williams, S. A. Lira et al., CX3CR1 regulates intestinal macrophage homeostasis, bacterial translocation, and colitogenic Th17 responses in mice, J Clin Invest, vol.121, pp.4787-4795, 2011.

B. Mehrad, M. P. Keane, and R. M. Strieter, Chemokines as mediators of angiogenesis, Thromb Haemost, vol.97, pp.755-762, 2007.

Y. Meng, M. A. Beckett, H. Liang, H. J. Mauceri, N. Van-rooijen et al., Blockade of tumor necrosis factor alpha signaling in tumorassociated macrophages as a radiosensitizing strategy, Cancer Res, vol.70, pp.1534-1543, 2010.

R. J. Miller, G. Banisadr, and B. J. Bhattacharyya, CXCR4 signaling in the regulation of stem cell migration and development, J Neuroimmunol, vol.198, pp.31-38, 2008.

J. B. Mitchem, D. J. Brennan, B. L. Knolhoff, B. A. Belt, Y. Zhu et al., Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses, Cancer Res, vol.73, pp.1128-1141, 2013.

S. K. Mittal and P. A. Roche, Suppression of antigen presentation by IL-10, Curr Opin Immunol, vol.34, pp.22-27, 2015.

K. Mizutani, S. Sud, N. A. Mcgregor, G. Martinovski, B. T. Rice et al., The chemokine CCL2 increases prostate tumor growth and bone metastasis through macrophage and osteoclast recruitment, Neoplasia, vol.11, pp.1235-1242, 2009.

A. J. Montero, M. Escobar, G. Lopes, S. Gluck, and C. Vogel, Bevacizumab in the treatment of metastatic breast cancer: friend or foe?, Curr Oncol Rep, vol.14, pp.1-11, 2012.

K. Movahedi, D. Laoui, C. Gysemans, M. Baeten, G. Stange et al., Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes, Cancer Res, vol.70, pp.5728-5739, 2010.

R. Mukherjee, P. Kanti-barman, P. Kumar-thatoi, R. Tripathy, B. Kumar-das et al., Non-Classical monocytes display inflammatory features: Validation in Sepsis and Systemic, Lupus Erythematous. Sci Rep, vol.5, p.13886, 2015.

A. Muller, B. Homey, H. Soto, N. Ge, D. Catron et al., Involvement of chemokine receptors in breast cancer metastasis, Nature, vol.410, pp.50-56, 2001.

C. Murdoch, A. Giannoudis, L. , and C. E. , Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues, Blood, vol.104, pp.2224-2234, 2004.

C. Murdoch, M. Muthana, S. B. Coffelt, L. , and C. E. , The role of myeloid cells in the promotion of tumour angiogenesis, Nat Rev Cancer, vol.8, pp.618-631, 2008.

P. M. Murphy, M. Baggiolini, I. F. Charo, C. A. Hebert, R. Horuk et al., International union of pharmacology. XXII. Nomenclature for chemokine receptors, Pharmacol Rev, vol.52, pp.145-176, 2000.
URL : https://hal.archives-ouvertes.fr/hal-00399158

P. J. Murray, J. E. Allen, S. K. Biswas, E. A. Fisher, D. W. Gilroy et al., Macrophage activation and polarization: nomenclature and experimental guidelines, Immunity, vol.41, pp.14-20, 2014.

M. Nahrendorf, F. K. Swirski, E. Aikawa, L. Stangenberg, T. Wurdinger et al., The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions, J Exp Med, vol.204, pp.3037-3047, 2007.

A. Nakamura, R. Ebina-shibuya, A. Itoh-nakadai, A. Muto, H. Shima et al., Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function, J Exp Med, vol.210, pp.2191-2204, 2013.

R. P. Negus, L. Turner, F. Burke, and F. R. Balkwill, Hypoxia down-regulates MCP1 expression: implications for macrophage distribution in tumors, J Leukoc Biol, vol.63, pp.758-765, 1998.

P. J. Nelson and A. M. Krensky, Chemokines, chemokine receptors, and allograft rejection, Immunity, vol.14, pp.377-386, 2001.

M. L. Novak and T. J. Koh, Macrophage phenotypes during tissue repair, J Leukoc Biol, vol.93, pp.875-881, 2013.

A. Nowicki, J. Szenajch, G. Ostrowska, A. Wojtowicz, K. Wojtowicz et al., Impaired tumor growth in colony-stimulating factor 1 (CSF-1)-deficient, macrophage-deficient op/op mouse: evidence for a role of CSF-1-dependent macrophages in formation of tumor stroma, Int J Cancer, vol.65, pp.112-119, 1996.

R. Noy and J. W. Pollard, Tumor-associated macrophages: from mechanisms to therapy, Immunity, vol.41, pp.49-61, 2014.

A. Oberg, S. Samii, R. Stenling, and G. Lindmark, Different occurrence of CD8+, CD45R0+, and CD68+ immune cells in regional lymph node metastases from colorectal cancer as potential prognostic predictors, Int J Colorectal Dis, vol.17, pp.25-29, 2002.

G. Obmolova, A. Teplyakov, T. J. Malia, T. L. Grygiel, R. Sweet et al., Structural basis for high selectivity of anti-CCL2 neutralizing antibody CNTO 888, Mol Immunol, vol.51, pp.227-233, 2012.

M. Ohta, F. Tanaka, H. Yamaguchi, N. Sadanaga, H. Inoue et al., The high expression of Fractalkine results in a better prognosis for colorectal cancer patients, Int J Oncol, vol.26, pp.41-47, 2005.

R. K. Pachynski, S. W. Wu, M. D. Gunn, and D. J. Erle, Secondary lymphoid-tissue Immunol, vol.161, pp.952-956, 1998.

R. T. Palframan, P. D. Collins, T. J. Williams, and S. M. Rankin, Eotaxin induces a rapid release of eosinophils and their progenitors from the bone marrow, Blood, vol.91, pp.2240-2248, 1998.

K. Pantel and R. H. Brakenhoff, Dissecting the metastatic cascade, Nat Rev Cancer, vol.4, pp.448-456, 2004.

R. C. Paolicelli, G. Bolasco, F. Pagani, L. Maggi, M. Scianni et al., Synaptic pruning by microglia is necessary for normal brain development, Science, vol.333, pp.1456-1458, 2011.

A. Parihar, T. D. Eubank, and A. I. Doseff, Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death, J Innate Immun, vol.2, pp.204-215, 2010.

B. Passlick, D. Flieger, and H. W. Ziegler-heitbrock, Identification and characterization of a novel monocyte subpopulation in human peripheral blood, Blood, vol.74, pp.2527-2534, 1989.

A. A. Patel, Y. Zhang, J. N. Fullerton, L. Boelen, A. Rongvaux et al., The fate and lifespan of human monocyte subsets in steady state and systemic inflammation, J Exp Med, vol.214, pp.1913-1923, 2017.

P. Paulus, E. R. Stanley, R. Schafer, D. Abraham, A. et al., Colonystimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts, Cancer Res, vol.66, pp.4349-4356, 2006.

J. Pease and R. Horuk, Chemokine receptor antagonists, J Med Chem, vol.55, pp.9363-9392, 2012.

L. Peiser, G. , and S. , The function of scavenger receptors expressed by macrophages and their role in the regulation of inflammation, Microbes Infect, vol.3, pp.149-159, 2001.

F. Piaggio, V. Kondylis, F. Pastorino, D. Di-paolo, P. Perri et al., A novel liposomal Clodronate depletes tumor-associated macrophages in primary and metastatic melanoma: Anti-angiogenic and anti-tumor effects, J Control Release, vol.223, pp.165-177, 2016.

F. Porcheray, S. Viaud, A. C. Rimaniol, C. Leone, B. Samah et al., Macrophage activation switching: an asset for the resolution of inflammation, Clin Exp Immunol, vol.142, pp.481-489, 2005.

L. Poupel, A. Boissonnas, P. Hermand, K. Dorgham, E. Guyon et al., Pharmacological inhibition of the chemokine receptor, CX3CR1, reduces atherosclerosis in mice, Arterioscler Thromb Vasc Biol, vol.33, pp.2297-2305, 2013.

E. M. Prescott and N. J. Proudfoot, Transcriptional collision between convergent genes in budding yeast, Proc Natl Acad Sci U S A, vol.99, pp.8796-8801, 2002.

S. Radoja, T. D. Rao, D. Hillman, and A. B. Frey, Mice bearing late-stage tumors have normal functional systemic T cell responses in vitro and in vivo, J Immunol, vol.164, pp.2619-2628, 2000.

L. Rajagopalan, R. , and K. , Structural basis of chemokine receptor function-a model for binding affinity and ligand selectivity, Biosci Rep, vol.26, pp.325-339, 2006.

G. J. Randolph, K. Inaba, D. F. Robbiani, R. M. Steinman, and W. A. Muller, Differentiation of phagocytic monocytes into lymph node dendritic cells in vivo, Immunity, vol.11, pp.753-761, 1999.

G. J. Randolph, C. Jakubzick, and C. Qu, Antigen presentation by monocytes and monocyte-derived cells, Curr Opin Immunol, vol.20, pp.52-60, 2008.

G. J. Randolph, G. Sanchez-schmitz, R. M. Liebman, and K. Schakel, The CD16(+) (FcgammaRIII(+)) subset of human monocytes preferentially becomes migratory dendritic cells in a model tissue setting, J Exp Med, vol.196, pp.517-527, 2002.

E. R. Rayburn, S. J. Ezell, and R. Zhang, Anti-Inflammatory Agents for Cancer Therapy, Mol Cell Pharmacol, vol.1, pp.29-43, 2009.

M. I. Reinhold, F. P. Lindberg, D. Plas, S. Reynolds, M. G. Peters et al., , 1995.

, In vivo expression of alternatively spliced forms of integrin-associated protein (CD47), J Cell Sci, vol.108, pp.3419-3425

N. M. Reusser, H. J. Dalton, S. Pradeep, V. Gonzalez-villasana, N. B. Jennings et al., Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer, Cancer Biol Ther, vol.15, pp.1061-1067, 2014.

W. F. Rigby, M. Waugh, and R. F. Graziano, Regulation of human monocyte HLADR and CD4 antigen expression, and antigen presentation by 1,25-dihydroxyvitamin D3, Blood, vol.76, pp.189-197, 1990.

P. C. Rodriguez and A. C. Ochoa, Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives, Immunol Rev, vol.222, pp.180-191, 2008.

B. J. Rollins and J. S. Pober, Interleukin-4 induces the synthesis and secretion of MCP-1/JE by human endothelial cells, Am J Pathol, vol.138, pp.1315-1319, 1991.

D. Rossi and A. Zlotnik, The biology of chemokines and their receptors, Annu Rev Immunol, vol.18, pp.217-242, 2000.

B. Ruffell and L. M. Coussens, Macrophages and therapeutic resistance in cancer, Cancer Cell, vol.27, pp.462-472, 2015.

H. Saji, M. Koike, T. Yamori, S. Saji, M. Seiki et al., ). progression of breast carcinoma, Cancer, vol.92, pp.1085-1091, 2001.

R. Salcedo, M. L. Ponce, H. A. Young, K. Wasserman, J. M. Ward et al., Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression, Blood, vol.96, pp.34-40, 2000.

M. N. Saleh, S. J. Goldman, A. F. Lobuglio, A. C. Beall, H. Sabio et al., CD16+ monocytes in patients with cancer: spontaneous elevation and pharmacologic induction by recombinant human macrophage colony-stimulating factor, Blood, vol.85, pp.2910-2917, 1995.

M. Samstein, H. A. Schreiber, I. M. Leiner, B. Susac, M. S. Glickman et al., Essential yet limited role for CCR2(+) inflammatory monocytes during Mycobacterium tuberculosis-specific T cell priming, vol.2, p.1086, 2013.

S. K. Sandhu, K. Papadopoulos, P. C. Fong, A. Patnaik, C. Messiou 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, Cancer Chemother Pharmacol, vol.71, pp.1041-1050, 2013.

A. Schmall, H. M. Al-tamari, S. Herold, M. Kampschulte, A. Weigert et al., Macrophage and cancer cell cross-talk via CCR2 and CX3CR1 is a fundamental mechanism driving lung cancer, Am J Respir Crit Care Med, vol.191, pp.437-447, 2015.

R. D. Schreiber, L. J. Old, and M. J. Smyth, Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion, Science, vol.331, pp.1565-1570, 2011.

G. Sciume, A. Soriani, M. Piccoli, L. Frati, A. Santoni et al., , 2010.

, /CX3CL1 axis negatively controls glioma cell invasion and is modulated by transforming growth factor-beta1, Neuro Oncol, vol.12, pp.701-710

N. V. Serbina and E. G. Pamer, Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2, Nat Immunol, vol.7, pp.311-317, 2006.

B. Shang, Y. Liu, S. J. Jiang, Y. Liu, V. Shankaran et al., Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep 5, 15179, Nature, vol.410, pp.1107-1111, 2001.

C. Shi and E. G. Pamer, Monocyte recruitment during infection and inflammation, Nat Rev Immunol, vol.11, pp.762-774, 2011.

G. P. Sims, D. C. Rowe, S. T. Rietdijk, R. Herbst, and A. J. Coyle, HMGB1 and RAGE in inflammation and cancer, Annu Rev Immunol, vol.28, pp.367-388, 2010.

A. Steen, O. Larsen, S. Thiele, M. M. Rosenkilde, M. Stein et al., Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation, Front Immunol, vol.5, pp.287-292, 1992.

R. M. Strieter, J. A. Belperio, R. J. Phillips, and M. P. Keane, CXC chemokines in angiogenesis of cancer, Semin Cancer Biol, vol.14, pp.195-200, 2004.
DOI : 10.1016/j.semcancer.2003.10.006

C. Sunderkotter, T. Nikolic, M. J. Dillon, N. Van-rooijen, M. Stehling et al., Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response, J Immunol, vol.172, pp.4410-4417, 2004.

F. K. Swirski, M. Nahrendorf, M. Etzrodt, M. Wildgruber, V. Cortez-retamozo et al., , 2009.

, Identification of splenic reservoir monocytes and their deployment to inflammatory sites, Science, vol.325, pp.612-616

G. Szabo, C. L. Miller, and K. Kodys, Antigen presentation by the CD4 positive monocyte subset, J Leukoc Biol, vol.47, pp.111-120, 1990.

K. Tachibana, S. Hirota, H. Iizasa, H. Yoshida, K. Kawabata et al., The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract, Nature, vol.393, pp.591-594, 1998.

S. Tamoutounour, M. Guilliams, F. Montanana-sanchis, H. Liu, D. Terhorst et al., Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin, Immunity, vol.39, pp.925-938, 2013.

K. Tanaka, J. Kurebayashi, M. Sohda, T. Nomura, U. Prabhakar et al., The expression of monocyte chemotactic protein-1 in papillary thyroid carcinoma is correlated with lymph node metastasis and tumor recurrence, Thyroid, vol.19, pp.21-25, 2009.

Y. Tanino, D. R. Coombe, S. E. Gill, W. C. Kett, O. Kajikawa et al., Kinetics of chemokineglycosaminoglycan interactions control neutrophil migration into the airspaces of the lungs, J Immunol, vol.184, pp.2677-2685, 2010.

M. Tardaguila, E. Mira, M. A. Garcia-cabezas, A. M. Feijoo, M. Quintela-fandino et al., CX3CL1 promotes breast cancer via transactivation of the EGF pathway, Cancer Res, vol.73, pp.4461-4473, 2013.

B. Thaler, P. J. Hohensinner, K. A. Krychtiuk, P. Matzneller, L. Koller et al., Differential in vivo activation of monocyte subsets during low-grade inflammation through experimental endotoxemia in humans, Immunity, vol.6, pp.975-987, 2016.

L. Tian, W. Li, J. Wang, Y. Zhang, Y. Zheng et al., The CKLF1-C19 peptide attenuates allergic lung inflammation by inhibiting CCR3-and CCR4-mediated chemotaxis in a mouse model of asthma, Allergy, vol.66, pp.287-297, 2011.

C. S. Tsai, F. H. Chen, C. C. Wang, H. L. Huang, S. M. Jung et al., Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth, Int J Radiat Oncol Biol Phys, vol.68, pp.499-507, 2007.

C. L. Tsou, W. Peters, Y. Si, S. Slaymaker, A. M. Aslanian et al., Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites, J Clin Invest, vol.117, pp.902-909, 2007.

K. Vaahtomeri, M. Brown, R. Hauschild, I. De-vries, A. F. Leithner et al., Locally Triggered Release of the Chemokine CCL21, 2017.

, Promotes Dendritic Cell Transmigration across Lymphatic Endothelia, Cell Rep, vol.19, pp.902-909

J. Vakkila, M. T. Lotze, L. Van-de-laar, W. Saelens, S. De-prijck et al., Yolk Sac Macrophages, Fetal Liver, and Adult Monocytes Can Colonize an Empty Niche and Develop into Functional Tissue-Resident Macrophages, Bull World Health Organ, vol.4, pp.360-362, 1968.

M. A. Venneri, M. De-palma, M. Ponzoni, F. Pucci, C. Scielzo et al., Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer, Blood, vol.109, pp.5276-5285, 2007.

D. Vestweber, How leukocytes cross the vascular endothelium, Nat Rev Immunol, vol.15, pp.692-704, 2015.

D. A. Vignali, L. W. Collison, and C. J. Workman, How regulatory T cells work, Nat Rev Immunol, vol.8, pp.523-532, 2008.

A. Viola and A. D. Luster, Chemokines and their receptors: drug targets in immunity and inflammation, Annu Rev Pharmacol Toxicol, vol.48, pp.171-197, 2008.

N. Wang, H. Liang, and K. Zen, Molecular mechanisms that influence the macrophage m1-m2 polarization balance, Front Immunol, vol.5, p.614, 2014.

C. Weber, K. S. Weber, C. Klier, S. Gu, R. Wank et al., Specialized roles of the chemokine receptors CCR1 and CCR5 in the recruitment of monocytes and T(H)1-like/CD45RO(+) T cells, Blood, vol.97, pp.1144-1146, 2001.

M. Weber, R. Hauschild, J. Schwarz, C. Moussion, I. De-vries et al., Interstitial dendritic cell guidance by haptotactic chemokine gradients, Science, vol.339, pp.328-332, 2013.

S. H. Wei, I. Parker, M. J. Miller, and M. D. Cahalan, A stochastic view of lymphocyte motility and trafficking within the lymph node, Immunol Rev, vol.195, pp.136-159, 2003.

L. M. Weiner, J. I. Clark, M. Davey, W. S. Li, I. Garcia-de-palazzo et al., Phase I trial of 2B1, a bispecific monoclonal antibody targeting cerbB-2 and Fc gamma RIII, Cancer Res, vol.55, pp.4586-4593, 1995.

K. Weiskopf and I. L. Weissman, Macrophages are critical effectors of antibody therapies for cancer, MAbs, vol.7, pp.303-310, 2015.

J. Wyckoff, W. Wang, E. Y. Lin, Y. Wang, F. Pixley et al., A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors, Cancer Res, vol.64, pp.7022-7029, 2004.

J. Xu, J. Escamilla, S. Mok, J. David, S. Priceman et al., CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer, Cancer Res, vol.73, pp.2782-2794, 2013.

J. Xue, S. V. Schmidt, J. Sander, A. Draffehn, W. Krebs et al., Transcriptome-based network analysis reveals a spectrum model of human macrophage activation, Immunity, vol.40, pp.274-288, 2014.

H. Yi, C. Guo, X. Yu, D. Zuo, W. et al., Mouse CD11b+Gr-1+ myeloid cells can promote Th17 cell differentiation and experimental autoimmune encephalomyelitis, J Immunol, vol.189, pp.4295-4304, 2012.

S. Yona, K. W. Kim, Y. Wolf, A. Mildner, D. Varol et al., Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis, Immunity, vol.38, pp.79-91, 2013.

T. Yoshimura, K. Matsushima, S. Tanaka, E. A. Robinson, E. Appella et al., Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines, Proc Natl Acad Sci U S A, vol.84, pp.9233-9237, 1987.

T. Yoshimura, N. Yuhki, S. K. Moore, E. Appella, M. I. Lerman et al., , 1989.

, Full-length cDNA cloning, expression in mitogen-stimulated blood mononuclear leukocytes, and sequence similarity to mouse competence gene JE, FEBS Lett, vol.244, pp.487-493

H. Yu, M. Kortylewski, P. , and D. , Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment, Nat Rev Immunol, vol.7, pp.41-51, 2007.

A. M. Zawada, K. S. Rogacev, B. Rotter, P. Winter, R. R. Marell et al., SuperSAGE evidence for CD14++CD16+ monocytes as a third monocyte subset, Blood, vol.118, pp.50-61, 2011.

J. Zhang, L. Patel, and K. J. Pienta, CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis, Cytokine Growth Factor Rev, vol.21, pp.41-48, 2010.

J. Zheng, M. Yang, J. Shao, Y. Miao, J. Han et al., Lipopolysaccharide-induced M2 to M1 macrophage transformation for IL-12p70 production is blocked by Candida albicans mediated up-regulation of EBI3 expression, Mol Cancer, vol.12, pp.323-338, 2013.

L. Zitvogel, L. Apetoh, F. Ghiringhelli, and G. Kroemer, Immunological aspects of cancer chemotherapy, Nat Rev Immunol, vol.8, pp.59-73, 2008.

A. Zlotnik, A. M. Burkhardt, and B. Homey, Homeostatic chemokine receptors and organ-specific metastasis, Nat Rev Immunol, vol.11, pp.597-606, 2011.

A. Zlotnik, Y. , and O. , Chemokines: a new classification system and their role in immunity, Immunity, vol.12, pp.121-127, 2000.

Y. R. Zou, A. H. Kottmann, M. Kuroda, I. Taniuchi, and D. R. Littman, Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development, Nature, vol.393, pp.595-599, 1998.