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
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 immuni...
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MDPI AG
2019-05-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/5/654 |
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| author | Veronika Caisova Liping Li Garima Gupta Ivana Jochmanova Abhishek Jha Ondrej Uher Thanh-Truc Huynh Markku Miettinen Ying Pang Luma Abunimer Gang Niu Xiaoyuan Chen Hans Kumar Ghayee David Taïeb Zhengping Zhuang Jan Zenka Karel Pacak |
| author_facet | Veronika Caisova Liping Li Garima Gupta Ivana Jochmanova Abhishek Jha Ondrej Uher Thanh-Truc Huynh Markku Miettinen Ying Pang Luma Abunimer Gang Niu Xiaoyuan Chen Hans Kumar Ghayee David Taïeb Zhengping Zhuang Jan Zenka Karel Pacak |
| author_sort | Veronika Caisova |
| collection | DOAJ |
| description | 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<sup>+</sup> 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. |
| first_indexed | 2024-03-12T10:52:44Z |
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| id | doaj.art-a3ffa00498a04078acc70eee28d851ee |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T10:52:44Z |
| publishDate | 2019-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a3ffa00498a04078acc70eee28d851ee2023-09-02T06:47:50ZengMDPI AGCancers2072-66942019-05-0111565410.3390/cancers11050654cancers11050654The Significant Reduction or Complete Eradication of Subcutaneous and Metastatic Lesions in a Pheochromocytoma Mouse Model after Immunotherapy Using Mannan-BAM, TLR Ligands, and Anti-CD40Veronika Caisova0Liping Li1Garima Gupta2Ivana Jochmanova3Abhishek Jha4Ondrej Uher5Thanh-Truc Huynh6Markku Miettinen7Ying Pang8Luma Abunimer9Gang Niu10Xiaoyuan Chen11Hans Kumar Ghayee12David Taïeb13Zhengping Zhuang14Jan Zenka15Karel Pacak16Section on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USASection on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USASection on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USASection on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USASection on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USASection on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USASection on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USALaboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USASection on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USASection on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USALaboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20814, USALaboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20814, USABiological Molecular Imaging Section, University of Florida College of Medicine, Gainesville, FL 32603, USADepartment of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, 13385 Marseille, FranceSurgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20814, USADepartment of Medical Biology, Faculty of Science, University of South Bohemia, Ceske Budejovice 37005, Czech RepublicSection on Medical Neuroendocrinology, <i>Eunice Kennedy Shriver</i> National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USATherapeutic 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<sup>+</sup> 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.https://www.mdpi.com/2072-6694/11/5/654pheochromocytomaparagangliomametastaticimmunotherapyinnate immunityadaptive immunitytoll-like receptorpathogen-associated molecular patternsneutrophilT cell |
| spellingShingle | Veronika Caisova Liping Li Garima Gupta Ivana Jochmanova Abhishek Jha Ondrej Uher Thanh-Truc Huynh Markku Miettinen Ying Pang Luma Abunimer Gang Niu Xiaoyuan Chen Hans Kumar Ghayee David Taïeb Zhengping Zhuang Jan Zenka Karel Pacak 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 pheochromocytoma paraganglioma metastatic immunotherapy innate immunity adaptive immunity toll-like receptor pathogen-associated molecular patterns neutrophil T cell |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | pheochromocytoma paraganglioma metastatic immunotherapy innate immunity adaptive immunity toll-like receptor pathogen-associated molecular patterns neutrophil T cell |
| url | https://www.mdpi.com/2072-6694/11/5/654 |
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