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Theranostics 2020; 10(2):925-937. doi:10.7150/thno.35989 This issue Cite

Research Paper

Cancer immunotherapy is accompanied by distinct metabolic patterns in primary and secondary lymphoid organs observed by non-invasive in vivo ¹⁸F-FDG-PET

Johannes Schwenck^1,2,3*, Barbara Schörg^2*, Francesco Fiz^1,4, Dominik Sonanini^2,5, Andrea Forschner⁶, Thomas Eigentler⁶, Benjamin Weide⁶, Manuela Martella⁷, Irene Gonzalez-Menendez^3,7, Cristina Campi⁸, Gianmario Sambuceti⁹, Ferdinand Seith¹⁰, Leticia Quintanilla-Martinez^3,7, Claus Garbe⁶, Christina Pfannenberg¹⁰, Martin Röcken^3,6,11, Christian la Fougere^1,3,11, Bernd J Pichler^2,3,11, Manfred Kneilling^2,3,6✉

1. Department of Nuclear Medicine and Clinical Molecular Imaging, Eberhard Karls University, 72076 Tübingen, Germany
2. Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, 72076 Tübingen, Germany
3. Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", Eberhard Karls University, 72076 Tübingen, Germany
4. Department of Internal Medicine, University of Genoa, Italy
5. Department of Internal Medicine II, Eberhard Karls University, 72076 Tübingen, Germany
6. Department of Dermatology, Eberhard Karls University, 72076 Tübingen, Germany
7. Institute of Pathology and Neuropathology and Comprehensive Cancer Center Tübingen, Eberhard Karls University, 72076 Tübingen, Germany
8. Department of Mathematics "Tullio Levi-Civita", University of Padua, Italy
9. Nuclear Medicine Unit, Department of Health Sciences, University of Genoa, Italy
10. Department of Diagnostic and Interventional Radiology, Eberhard Karls University, 72076 Tübingen, Germany
11. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site Tübingen, 72076 Tübingen, Germany
* Contributed equally

✉ Corresponding author: manfred.kneillinguni-tuebingen.de telephone: +49-7071-29-83427 fax: +49-7071-29-4451

Abstract

Purpose: Cancer immunotherapy depends on a systemic immune response, but the basic underlying mechanisms are still largely unknown. Despite the very successful and widespread use of checkpoint inhibitors in the clinic, the majority of cancer patients do not benefit from this type of treatment. In this translational study, we investigated whether noninvasive in vivo positron emission tomography (PET) imaging using 2-[¹⁸F]fluoro-2-deoxy-D-glucose (¹⁸F-FDG) is capable of detecting immunotherapy-associated metabolic changes in the primary and secondary lymphoid organs and whether this detection enables the prediction of a successful anti-cancer immune response.

Methods: RIP1-Tag2 mice with progressed endogenous insular cell carcinomas underwent a combined cancer immunotherapy consisting of CD4⁺ T cells plus monoclonal antibodies (mAbs) against programmed death ligand-1 (PD-L1) and lymphocyte activation gene-3 (LAG-3) or a sham treatment after radiation-mediated immune cell depletion. A second cohort of RIP1-Tag2 mice underwent exclusive checkpoint inhibitor therapy (CIT) using anti-PD-L1/LAG-3 mAbs or sham treatment without initial immune cell depletion to mimic the clinical situation.

All mice were monitored by ¹⁸F-FDG-PET combined with anatomical magnetic resonance imaging (MRI). In addition, we retrospectively analyzed PET / computed tomography (CT) scans (PET/CT) regarding ¹⁸F-FDG uptake of CIT-treated metastatic melanoma patients in the spleen (n=23) and bone marrow (BM; n=20) as well as blood parameters (n=17-21).

Results: RIP1-Tag2 mice with advanced insular cell carcinomas treated with combination immunotherapy exhibited significantly increased ¹⁸F-FDG uptake in the spleen compared to sham-treated mice. Histopathology of the spleens from treated mice revealed atrophy of the white pulp with fewer germinal centers and an expanded red pulp with hyperplasia of neutrophils than those of sham-treated mice. Immunohistochemistry and flow cytometry analyses of the spleens revealed a lower number of T cells and a higher number of neutrophils compared to those in the spleens of sham-treated mice. Flow cytometry of the BM showed enhanced activation of T cells following the treatment schemes that included checkpoint inhibitors. The ratio of ¹⁸F-FDG uptake at baseline to the uptake at follow-up in the spleens of exclusively CIT-treated RIP1-Tag2 mice was significantly enhanced, but the ratio was not enhanced in the spleens of the sham-treated littermates. Flow cytometry analysis confirmed a reduced number of T cells in the spleens of exclusively CIT-treated mice compared to that of sham-treated mice. A retrospective analysis of clinical ¹⁸F-FDG-PET/CT scans revealed enhanced ¹⁸F-FDG uptake in the spleens of some successfully CIT-treated patients with metastatic melanoma, but there were no significant differences between responders and non-responders. The analysis of the BM in clinical ¹⁸F-FDG-PET/CT scans with a computational segmentation tool revealed significantly higher baseline ¹⁸F-FDG uptake in patients who responded to CIT than in non-responders, and this relationship was independent of bone metastasis, even in the baseline scan.

Conclusions: Thus, we are presenting the first translational study of solid tumors focusing on the metabolic patterns of primary and secondary lymphoid organs induced by the systemic immune response after CIT. We demonstrate that the widely available ¹⁸F-FDG-PET modality is an applicable translational tool that has high potential to stratify patients at an early time point.

Keywords: Checkpoint inhibitor therapy, response assessment of immunotherapy, PET/CT, translational, imaging of primary and secondary lymphatic organs

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