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Cancers (Basel). 2019 May 11;11(5). pii: E654. doi: 10.3390/cancers11050654.

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.

Author information

1
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. veronika.caisova@nih.gov.
2
Department of Medical Biology, Faculty of Science, University of South Bohemia, Ceske Budejovice 37005, Czech Republic. veronika.caisova@nih.gov.
3
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. bat.150@hotmail.com.
4
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. garima.gupta83@gmail.com.
5
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. ivana.jochmanova@gmail.com.
6
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. abhishek.jha@nih.gov.
7
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. ondrej.uher@nih.gov.
8
Department of Medical Biology, Faculty of Science, University of South Bohemia, Ceske Budejovice 37005, Czech Republic. ondrej.uher@nih.gov.
9
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. huynht@mail.nih.gov.
10
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA. markku.miettinen@nih.gov.
11
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. ying.pang@nih.gov.
12
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. luma.abunimer@nih.gov.
13
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20814, USA. gang.niu@nih.gov.
14
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20814, USA. shawn.chen@nih.gov.
15
Biological Molecular Imaging Section, University of Florida College of Medicine, Gainesville, FL 32603, USA. Hans.Ghayee@medicine.ufl.edu.
16
Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, 13385 Marseille, France. David.TAIEB@ap-hm.fr.
17
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USA. zhengping.zhuang@nih.gov.
18
Department of Medical Biology, Faculty of Science, University of South Bohemia, Ceske Budejovice 37005, Czech Republic. jzenka@gmail.com.
19
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA. karel@mail.nih.gov.

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.

KEYWORDS:

T cell; adaptive immunity; immunotherapy; innate immunity; metastatic; neutrophil; paraganglioma; pathogen-associated molecular patterns; pheochromocytoma; toll-like receptor

PMID:
31083581
DOI:
10.3390/cancers11050654
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