PMID- 26459350
OWN - NLM
STAT- MEDLINE
DCOM- 20160226
LR  - 20240210
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 195
IP  - 10
DP  - 2015 Nov 15
TI  - Oncogenic Transformation of Dendritic Cells and Their Precursors Leads to Rapid 
      Cancer Development in Mice.
PG  - 5066-76
LID - 10.4049/jimmunol.1500889 [doi]
AB  - 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 Clec9a(Kras-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 Clec9a(Kras-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 Clec9a(Kras-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.
CI  - Copyright (c) 2015 The Authors.
FAU - Bottcher, Jan P
AU  - Bottcher JP
AD  - Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields 
      Laboratory, London WC2A 3LY, United Kingdom.
FAU - Zelenay, Santiago
AU  - Zelenay S
AD  - Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields 
      Laboratory, London WC2A 3LY, United Kingdom.
FAU - Rogers, Neil C
AU  - Rogers NC
AD  - Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields 
      Laboratory, London WC2A 3LY, United Kingdom.
FAU - Helft, Julie
AU  - Helft J
AD  - Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields 
      Laboratory, London WC2A 3LY, United Kingdom.
FAU - Schraml, Barbara U
AU  - Schraml BU
AD  - Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields 
      Laboratory, London WC2A 3LY, United Kingdom.
FAU - Reis e Sousa, Caetano
AU  - Reis e Sousa C
AD  - Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields 
      Laboratory, London WC2A 3LY, United Kingdom caetano@crick.ac.uk.
LA  - eng
GR  - 15689/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20151012
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Clec9a protein, mouse)
RN  - 0 (Lectins, C-Type)
RN  - 0 (Receptors, Immunologic)
RN  - EC 3.6.5.2 (Hras protein, mouse)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Animals
MH  - Cell Transformation, Neoplastic/genetics/*immunology/pathology
MH  - Dendritic Cells/*immunology/pathology
MH  - Lectins, C-Type/genetics/immunology
MH  - Mice
MH  - Mice, Transgenic
MH  - Neoplasms, Experimental/genetics/*immunology/pathology
MH  - Proto-Oncogene Proteins p21(ras)/genetics/immunology
MH  - Rats
MH  - Receptors, Immunologic/genetics/immunology
MH  - Stem Cells/*immunology/pathology
PMC - PMC4635568
EDAT- 2015/10/16 06:00
MHDA- 2016/02/27 06:00
PMCR- 2015/10/12
CRDT- 2015/10/14 06:00
PHST- 2015/04/16 00:00 [received]
PHST- 2015/09/15 00:00 [accepted]
PHST- 2015/10/14 06:00 [entrez]
PHST- 2015/10/16 06:00 [pubmed]
PHST- 2016/02/27 06:00 [medline]
PHST- 2015/10/12 00:00 [pmc-release]
AID - jimmunol.1500889 [pii]
AID - ji_1500889 [pii]
AID - 10.4049/jimmunol.1500889 [doi]
PST - ppublish
SO  - J Immunol. 2015 Nov 15;195(10):5066-76. doi: 10.4049/jimmunol.1500889. Epub 2015 
      Oct 12.