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Theranostics 2019; 9(20):5869-5885. doi:10.7150/thno.33275 This issue Cite

Research Paper

Visualization and quantification of in vivo homing kinetics of myeloid-derived suppressor cells in primary and metastatic cancer

Sabrina H. L. Hoffmann¹, Dorothea I. Reck¹, Andreas Maurer^1,2, Birgit Fehrenbacher³, Jaclyn E. Sceneay⁴, Marilena Poxleitner¹, Hasan H. Öz⁵, Walter Ehrlichmann¹, Gerald Reischl^1,2, Kerstin Fuchs¹, Martin Schaller³, Dominik Hartl⁵, Manfred Kneilling^1,2,3, Andreas Möller⁴, Bernd J. Pichler^1,2,6✉, Christoph M. Griessinger¹

1. Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University Tübingen, Tübingen, Germany
2. iFIT-Cluster of Excellence, University of Tübingen, Germany
3. Department of Dermatology, Eberhard Karls University Tübingen, Tübingen, Germany
4. Tumor Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Australia
5. Children's Hospital, University of Tübingen, Tübingen, Germany
6. German Cancer Consortium (DKTK), Partner Site Tübingen; German Cancer Research Center (DKFZ), Heidelberg, Germany

✉ Corresponding author: Bernd J. Pichler (bernd.pichleruni-tuebingen.de), Address: Röntgenweg 13, 72076 Tübingen, Germany, Tel: +49 7071 29 83427

Abstract

Myeloid-derived suppressor cells (MDSCs) are immunosuppressive cells of the myeloid compartment and major players in the tumor microenvironment (TME). With increasing numbers of studies describing MDSC involvement in cancer immune escape, cancer metastasis and the dampening of immunotherapy responses, MDSCs are of high interest in current cancer therapy research. Although heavily investigated in the last decades, the in vivo migration dynamics of MDSC subpopulations in tumor- or metastases-bearing mice have not yet been studied extensively. Therefore, we have modified our previously reported intracellular cell labeling method and applied it to in vitro generated MDSCs for the quantitative in vivo monitoring of MDSC migration in primary and metastatic cancer. MDSC migration to primary cancers was further correlated to the frequency of endogenous MDSCs. Methods: Utilizing a ⁶⁴Cu-labeled 1,4,7-triazacyclononane-triacetic acid (NOTA)-modified CD11b-specific monoclonal antibody (mAb) (clone M1/70), we were able to label in vitro generated polymorphonuclear (PMN-) and monocytic (M-) MDSCs for positron emission tomography (PET) imaging. Radiolabeled PMN- and M-MDSCs ([⁶⁴Cu]PMN-MDSCs and [⁶⁴Cu]M-MDSCs, respectively) were then adoptively transferred into primary and metastatic MMTV-PyMT-derived (PyMT-) breast cancer- and B16F10 melanoma-bearing experimental animals, and static PET and anatomical magnetic resonance (MR) images were acquired 3, 24 and 48 h post cell injection. Results: The internalization of the [⁶⁴Cu]NOTA-mAb-CD11b-complex was completed within 3 h, providing moderately stable radiolabeling with little detrimental effect on cell viability and function as determined by Annexin-V staining and T cell suppression in flow cytometric assays. Further, we could non-invasively and quantitatively monitor the migration and tumor homing of both [⁶⁴Cu]NOTA-αCD11b-mAb-labeled PMN- and M-MDSCs in mouse models of primary and metastatic breast cancer and melanoma by PET. We were able to visualize and quantify an increased migration of adoptively transferred [⁶⁴Cu]M-MDSCs than [⁶⁴Cu]PMN-MDSCs to primary breast cancer lesions. The frequency of endogenous MDSCs in the PyMT breast cancer and B16F10 melanoma model correlated to the uptake values of adoptively transferred MDSCs with higher frequencies of PMN- and M-MDSCs in the more aggressive B16F10 melanoma tumors. Moreover, aggressively growing melanomas and melanoma-metastatic lesions recruited higher percentages of both [⁶⁴Cu]PMN- and [⁶⁴Cu]M-MDSCs than primary and metastatic breast cancer lesions as early as 24 h post adoptive MDSC transfer, indicating an overall stronger recruitment of cancer-promoting immunosuppressive MDSCs. Conclusion: Targeting of the cell surface integrin CD11b with a radioactive mAb is feasible for labeling of murine MDSCs for PET imaging. Fast internalization of the [⁶⁴Cu]NOTA-αCD11b-mAb provides presumably enhanced stability while cell viability and functionality was not significantly affected. Moreover, utilization of the CD11b-specific mAb allows for straightforward adaptation of the labeling approach for in vivo molecular imaging of other myeloid cells of interest in cancer therapy, including monocytes, macrophages or neutrophils.

Keywords: Myeloid-derived suppressor cells, cancer, cell tracking, positron emission tomography

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