title: Optical in vivo imaging of the alarmin S100A9 in tumor lesions allows for estimation of the individual malignant potential by evaluation of tumor-host cell interaction.
abstract: Tumors recruit and reprogram immune cells to support tumor development and spread, the most prominent among them being of monocytic origin such as tumor-associated macrophages (TAM) or myeloid-derived suppressor cells (MDSC). The alarmin S100A8/A9 has been implicated in the induction of TAM and MDSC. We assessed S100A9 as a molecular imaging marker for the activity of tumor-associated immune cells in a syngeneic murine breast cancer model. S100A9 could serve as a surrogate marker for tumor immune crosstalk as a function of malignancy, providing a tool with the potential for both basic research in tumor immunology and clinical stratification of patients.
  
  
  METHODS
  BALB/c mice were inoculated with murine breast cancer cells of common origin but different metastatic capability. At different times during tumor development, optical imaging was performed using a S100A9-specific probe to visualize activated monocytes. To further explore the impact of tumor-educated monocytes, splenic myeloid cells were isolated from either healthy or tumor-bearing animals and injected into tumor-bearing mice. We analyzed the effect of the cell transfer on immune cell activity and tumor development.
  
  
  RESULTS
  We could prove S100A9-driven imaging to sensitively and specifically reflect monocyte activity in primary tumor lesions. The imaging results were corroborated by histology and fluorescence-activated cell sorting analyses. In a prospective experiment, S100A9 imaging proved indicative of the individual tumor growth, with excellent correlation. Moreover, we could show that the monocyte activity as depicted by S100A9 activity in the primary tumor lesion mirrored the tumor's metastatic behavior. Treatment with tumor-primed splenic monocytes induced increased tumor growth, accompanied by an augmented infiltration of activated myeloid cells (MDSC and TAM) into the tumor. The consecutive S100A9 expression as depicted by in vivo imaging was significantly increased.
  
  
  CONCLUSIONS
  S100A9 proved to be a sensitive and specific marker for the activity of tumor-associated immune cells. To our knowledge, S100A9 imaging represents a first in vivo imaging approach for the estimation of recruitment and activity of tumor-associated myeloid immune cells. We demonstrated the potential value of this imaging approach for prediction of local and systemic tumor development.
authors: Department of Clinical Radiology, University Hospital Münster, Münster, Germany.
authors: Anne
authors: A
authors: Becker
authors: Department of Clinical Radiology, University Hospital Münster, Münster, Germany.
authors: Nils
authors: N
authors: Große Hokamp
authors: Institute of Immunology, University Hospital Münster, Münster, Germany.
authors: Stefanie
authors: S
authors: Zenker
authors: Richard Dimbleby Department of Cancer Research, King's College London, London, United Kingdom Breakthrough Breastcancer Unit, Guy's and St. Thomas' NHS Hospital Trust, London, United Kingdom.
authors: Fabian
authors: F
authors: Flores-Borja
authors: Institute of Immunology, University Hospital Münster, Münster, Germany.
authors: Katarzyna
authors: K
authors: Barzcyk
authors: Department of Paediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.
authors: Georg
authors: G
authors: Varga
authors: Institute of Immunology, University Hospital Münster, Münster, Germany Interdisciplinary Center for Clinical Research, Münster University, Münster, Germany.
authors: Johannes
authors: J
authors: Roth
authors: Department of Clinical Radiology, University Hospital Münster, Münster, Germany Interdisciplinary Center for Clinical Research, Münster University, Münster, Germany.
authors: Christiane
authors: C
authors: Geyer
authors: Department of Clinical Radiology, University Hospital Münster, Münster, Germany.
authors: Walter
authors: W
authors: Heindel
authors: Interdisciplinary Center for Clinical Research, Münster University, Münster, Germany Department of Radiology, St. Franziskus Hospital GmbH Münster, Münster, Germany; and.
authors: Christoph
authors: C
authors: Bremer
authors: Institute of Immunology, University Hospital Münster, Münster, Germany Interdisciplinary Center for Clinical Research, Münster University, Münster, Germany.
authors: Thomas
authors: T
authors: Vogl
authors: Department of Clinical Radiology, University Hospital Münster, Münster, Germany Richard Dimbleby Department of Cancer Research, King's College London, London, United Kingdom Division of Imaging Sciences and Biomedical Engineering, King's College London, London, United Kingdom michel.eisenblaetter@kcl.ac.uk.
authors: Michel
authors: M
authors: Eisenblaetter
mesh_terms: D000818:Animals; D040502:Calgranulin B / Q000378:metabolism*; D002232:Carbocyanines / Q000737:chemistry; D002450:Cell Communication; D049109:Cell Proliferation; D003952:Diagnostic Imaging / Q000379:methods*; D005260:Female; D007249:Inflammation / Q000473:pathology; D039841:Leukocyte L1 Antigen Complex / Q000737:chemistry; D008264:Macrophages / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000166:cytology; D022423:Myeloid Cells / Q000276:immunology; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D055095:Optics and Photonics; D051381:Rats
chemical_list: C098793:CY5.5 cyanine dye; D040502:Calgranulin B; D002232:Carbocyanines; D039841:Leukocyte L1 Antigen Complex
keywords: MRP8/MRP14; calprotectin; cancer; monocytes; optical imaging; tumor immunology; tumor-induced inflammation