Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma.
Valpha24-invariant natural killer T (NKT) cells are potentially important for antitumor immunity. We and others have previously demonstrated positive associations between NKT cell presence in primary tumors and long-term survival in distinct human cancers. However, the mechanism by which aggressive tumors avoid infiltration with NKT and other T cells remains poorly understood. Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in MYCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. Unlike other oncogenes, MYCN repressed chemokine expression in a STAT3-independent manner, requiring an E-box element in the CCL2 promoter to mediate transcriptional repression. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amplified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies.
Song
Liping
L
Division of Hematology-Oncology, Department of Pediatrics, Childrens Hospital Los Angeles (CHLA), Los Angeles, California 90027, USA.
Ara
Tasnim
T
Wu
Hong-Wei
HW
Woo
Chan-Wook
CW
Reynolds
C Patrick
CP
Seeger
Robert C
RC
DeClerck
Yves A
YA
Thiele
Carol J
CJ
Sposto
Richard
R
Metelitsa
Leonid S
LS
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D000071447:N-Myc Proto-Oncogene Protein; D009362:Neoplasm Metastasis / Q000473:pathology; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D018932:Chemokine CCL2; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D050796:STAT3 Transcription Factor
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