Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid Cancer Development in Mice

Dendritic cells (DCs) are powerful APCs that can induce Ag-specific adaptive immune responses and are increasingly recognized as important players in innate immunity to both infection and malignancy. Interestingly, although there are multiple described hematological malignancies, DC cancers are rare...

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Main Authors:	Böttcher, Jan P., Zelenay, Santiago, Rogers, Neil C., Helft, Julie, Schraml, Barbara U., Reis e Sousa, Caetano
Format:	Online
Language:	English
Published:	AAI 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635568/

id	pubmed-4635568
recordtype	oai_dc
spelling	pubmed-46355682015-11-09 Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid Cancer Development in Mice Böttcher, Jan P. Zelenay, Santiago Rogers, Neil C. Helft, Julie Schraml, Barbara U. Reis e Sousa, Caetano Tumor Immunology Dendritic cells (DCs) are powerful APCs that can induce Ag-specific adaptive immune responses and are increasingly recognized as important players in innate immunity to both infection and malignancy. Interestingly, although there are multiple described hematological malignancies, DC cancers are rarely observed in humans. Whether this is linked to the immunogenic potential of DCs, which might render them uniquely susceptible to immune control upon neoplastic transformation, has not been fully investigated. To address the issue, we generated a genetically engineered mouse model in which expression of Cre recombinase driven by the C-type lectin domain family 9, member a (Clec9a) locus causes expression of the Kirsten rat sarcoma viral oncogene homolog (Kras)G12D oncogenic driver and deletion of the tumor suppressor p53 within developing and differentiated DCs. We show that these Clec9aKras-G12D mice rapidly succumb from disease and display massive accumulation of transformed DCs in multiple organs. In bone marrow chimeras, the development of DC cancer could be induced by a small number of transformed cells and was not prevented by the presence of untransformed DCs. Notably, activation of transformed DCs did not happen spontaneously but could be induced upon stimulation. Although Clec9aKras-G12D mice showed altered thymic T cell development, peripheral T cells were largely unaffected during DC cancer development. Interestingly, transformed DCs were rejected upon adoptive transfer into wild-type but not lymphocyte-deficient mice, indicating that immunological control of DC cancer is in principle possible but does not occur during spontaneous generation in Clec9aKras-G12D mice. Our findings suggest that neoplastic transformation of DCs does not by default induce anti-cancer immunity and can develop unhindered by immunological barriers. AAI 2015-11-15 2015-10-12 /pmc/articles/PMC4635568/ /pubmed/26459350 http://dx.doi.org/10.4049/jimmunol.1500889 Text en Copyright © 2015 The Authors This is an open-access article distributed under the terms of the CC-BY 3.0 Unported license.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Böttcher, Jan P. Zelenay, Santiago Rogers, Neil C. Helft, Julie Schraml, Barbara U. Reis e Sousa, Caetano
spellingShingle	Böttcher, Jan P. Zelenay, Santiago Rogers, Neil C. Helft, Julie Schraml, Barbara U. Reis e Sousa, Caetano Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid Cancer Development in Mice
author_facet	Böttcher, Jan P. Zelenay, Santiago Rogers, Neil C. Helft, Julie Schraml, Barbara U. Reis e Sousa, Caetano
author_sort	Böttcher, Jan P.
title	Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid Cancer Development in Mice
title_short	Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid Cancer Development in Mice
title_full	Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid Cancer Development in Mice
title_fullStr	Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid Cancer Development in Mice
title_full_unstemmed	Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid Cancer Development in Mice
title_sort	oncogenic transformation of dendritic cells and their precursors leads to rapid cancer development in mice
description	Dendritic cells (DCs) are powerful APCs that can induce Ag-specific adaptive immune responses and are increasingly recognized as important players in innate immunity to both infection and malignancy. Interestingly, although there are multiple described hematological malignancies, DC cancers are rarely observed in humans. Whether this is linked to the immunogenic potential of DCs, which might render them uniquely susceptible to immune control upon neoplastic transformation, has not been fully investigated. To address the issue, we generated a genetically engineered mouse model in which expression of Cre recombinase driven by the C-type lectin domain family 9, member a (Clec9a) locus causes expression of the Kirsten rat sarcoma viral oncogene homolog (Kras)G12D oncogenic driver and deletion of the tumor suppressor p53 within developing and differentiated DCs. We show that these Clec9aKras-G12D mice rapidly succumb from disease and display massive accumulation of transformed DCs in multiple organs. In bone marrow chimeras, the development of DC cancer could be induced by a small number of transformed cells and was not prevented by the presence of untransformed DCs. Notably, activation of transformed DCs did not happen spontaneously but could be induced upon stimulation. Although Clec9aKras-G12D mice showed altered thymic T cell development, peripheral T cells were largely unaffected during DC cancer development. Interestingly, transformed DCs were rejected upon adoptive transfer into wild-type but not lymphocyte-deficient mice, indicating that immunological control of DC cancer is in principle possible but does not occur during spontaneous generation in Clec9aKras-G12D mice. Our findings suggest that neoplastic transformation of DCs does not by default induce anti-cancer immunity and can develop unhindered by immunological barriers.
publisher	AAI
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4635568/
_version_	1613498311329710080

Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid Cancer Development in Mice

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