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The Significant Reduction or Complete Eradication of Subcutaneous and Metastatic Lesions in a Pheochromocytoma Mouse Model after Immunotherapy Using Mannan-BAM, TLR Ligands, and Anti-CD40

1
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA
2
Department of Medical Biology, Faculty of Science, University of South Bohemia, Ceske Budejovice 37005, Czech Republic
3
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA
4
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20814, USA
5
Biological Molecular Imaging Section, University of Florida College of Medicine, Gainesville, FL 32603, USA
6
Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, 13385 Marseille, France
7
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 654; https://doi.org/10.3390/cancers11050654
Received: 13 March 2019 / Revised: 4 May 2019 / Accepted: 6 May 2019 / Published: 11 May 2019
(This article belongs to the Special Issue Pheochromocytoma (PHEO) and Paraganglioma (PGL))
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Abstract

Therapeutic options for metastatic pheochromocytoma/paraganglioma (PHEO/PGL) are limited. Here, we tested an immunotherapeutic approach based on intratumoral injections of mannan-BAM with toll-like receptor ligands into subcutaneous PHEO in a mouse model. This therapy elicited a strong innate immunity-mediated antitumor response and resulted in a significantly lower PHEO volume compared to the phosphate buffered saline (PBS)-treated group and in a significant improvement in mice survival. The cytotoxic effect of neutrophils, as innate immune cells predominantly infiltrating treated tumors, was verified in vitro. Moreover, the combination of mannan-BAM and toll-like receptor ligands with agonistic anti-CD40 was associated with increased mice survival. Subsequent tumor re-challenge also supported adaptive immunity activation, reflected primarily by long-term tumor-specific memory. These results were further verified in metastatic PHEO, where the intratumoral injections of mannan-BAM, toll-like receptor ligands, and anti-CD40 into subcutaneous tumors resulted in significantly less intense bioluminescence signals of liver metastatic lesions induced by tail vein injection compared to the PBS-treated group. Subsequent experiments focusing on the depletion of T cell subpopulations confirmed the crucial role of CD8+ T cells in inhibition of bioluminescence signal intensity of liver metastatic lesions. These data call for a new therapeutic approach in patients with metastatic PHEO/PGL using immunotherapy that initially activates innate immunity followed by an adaptive immune response. View Full-Text
Keywords: pheochromocytoma; paraganglioma; metastatic; immunotherapy; innate immunity; adaptive immunity; toll-like receptor; pathogen-associated molecular patterns; neutrophil; T cell pheochromocytoma; paraganglioma; metastatic; immunotherapy; innate immunity; adaptive immunity; toll-like receptor; pathogen-associated molecular patterns; neutrophil; T cell
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Caisova, V.; Li, L.; Gupta, G.; Jochmanova, I.; Jha, A.; Uher, O.; Huynh, T.-T.; Miettinen, M.; Pang, Y.; Abunimer, L.; Niu, G.; Chen, X.; Ghayee, H.K.; Taïeb, D.; Zhuang, Z.; Zenka, J.; Pacak, K. The Significant Reduction or Complete Eradication of Subcutaneous and Metastatic Lesions in a Pheochromocytoma Mouse Model after Immunotherapy Using Mannan-BAM, TLR Ligands, and Anti-CD40. Cancers 2019, 11, 654.

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