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Theranostics 2017; 7(9):2392-2401. doi:10.7150/thno.17138

Research Paper

Visualization of Tumor-Immune Interaction - Target-Specific Imaging of S100A8/A9 Reveals Pre-Metastatic Niche Establishment

Michel Eisenblaetter^{1, 2, 3*✉}, Fabian Flores-Borja^{1, 4*}, Jae Jin Lee^{1, 4}, Christina Wefers¹, Hannah Smith¹, Rebekka Hueting², Margaret S Cooper², Philip J Blower², Dominic Patel⁵, Manuel Rodriguez-Justo⁵, Hanna Milewicz⁶, Thomas Vogl⁷, Johannes Roth⁷, Andrew Tutt⁴, Tobias Schaeffter², Tony Ng^{1, 4, 6}

1. Richard Dimbleby Department of Cancer Research, Randall Division & Division of Cancer Studies, King's College London, London SE1 1UL, UK
2. Division of Imaging Sciences & Biomedical Engineering, King's College London, London SE1 7EH, UK
3. Department of Clinical Radiology, University Hospital Muenster, 48149 Muenster, Germany
4. Breast Cancer Now Research Unit, Department of Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK
5. Department of Histopathology, University College London, London WC1
6. UCL Cancer Institute, Paul O'Gorman Building, University College London, London WC1E 6DD, UK
7. Institute of Immunology, University Hospital Muenster, 48149 Muenster, Germany
* Michel Eisenblaetter and Fabian Flores-Borja contributed equally to this work.

Abstract

Background Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming.

Methods A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy.

Results S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p<0.001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r²=0.788; p<0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID).

Conclusion We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.

Keywords: Premetastatic niche, tumour immunology, imaging, MDSC.