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Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma
Liping Song, … , Richard Sposto, Leonid S. Metelitsa
Liping Song, … , Richard Sposto, Leonid S. Metelitsa
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2702-2712. https://doi.org/10.1172/JCI30751.
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Research Article Oncology

Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma

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Abstract

Vα24-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.

Authors

Liping Song, Tasnim Ara, Hong-Wei Wu, Chan-Wook Woo, C. Patrick Reynolds, Robert C. Seeger, Yves A. DeClerck, Carol J. Thiele, Richard Sposto, Leonid S. Metelitsa

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Figure 2

MYCNkd induces CCL2 expression in neuroblastoma cells and NKT cell chemoattraction.

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MYCNkd induces CCL2 expression in neuroblastoma cells and NKT cell chemo...
SK-N-BE(2) and LA-N-1 MYCN-amplified neuroblastoma cell lines were stably transduced with MYCN shRNA using a U6 expression cassette into pHIV-7-EGFP lentiviral plasmid. (A) Representative Western blot analysis of MYCN protein in the nuclear extracts from indicated cells. Lane 1, parental; lane 2, vector control; lane 3, MYCN shRNA. (B) CCL2 RNA expression was quantified by TaqMan RT-PCR; values are relative to expression in parental cells. Results are mean ± SD from 3 experiments. (C) CBA analysis was performed with supernatants of vector control or MYCN shRNA-transduced SK-N-BE(2) cells as described in Figure 1C. (D) Migration of freshly isolated PBLs to the neuroblastoma cell supernatants with the indicated conditions was performed as described in Figure 1C. Where indicated, supernatants were pretreated for 1 hour with neutralizing anti-CCL2, anti-CXCL8, or isotype control (IgG1) mAb. Results are mean ± SD from 3 experiments.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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