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PMID: 15123743 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2.

The Journal of experimental medicine ·Vol. 199 ·No. 9 ·2004-05-03 ·Pages 1213-21

Metelitsa LS, Wu HW, Wang H, Yang Y, Warsi Z, Asgharzadeh S, Groshen S, Wilson SB, Seeger RC

Abstract

CD1d-restricted Valpha24-Jalpha18-invariant natural killer T cells (iNKTs) are potentially important in tumor immunity. However, little is known about their localization to tumors. We analyzed 98 untreated primary neuroblastomas from patients with metastatic disease (stage 4) for tumor-infiltrating iNKTs using TaqMan((R)) reverse transcription polymerase chain reaction and immunofluorescent microscopy. 52 tumors (53%) contained iNKTs, and oligonucleotide microarray analysis of the iNKT(+) and iNKT(-) tumors revealed that the former expressed higher levels of CCL2/MCP-1, CXCL12/SDF-1, CCL5/RANTES, and CCL21/SLC. Eight tested neuroblastoma cell lines secreted a range of CCL2 (0-21.6 ng/ml), little CXCL12 (</=0.1 ng/ml), and no detectable CCL5 or CCL21. CCR2, the receptor for CCL2, was more frequently expressed by iNKT compared with natural killer and T cells from blood (P < 0.001). Supernatants of neuroblastoma cell lines that produced CCL2 induced in vitro migration of iNKTs from blood of patients and normal adults; this was abrogated by an anti-CCL2 monoclonal antibody. CCL2 expression by tumors was found to inversely correlate with MYCN proto-oncogene amplification and expression (r = 0.5, P < 0.001), and MYCN-high/CCL2-low expression accurately predicted the absence of iNKTs (P < 0.001). In summary, iNKTs migrate toward neuroblastoma cells in a CCL2-dependent manner, preferentially infiltrating MYCN nonamplified tumors that express CCL2.

MeSH Terms
Antineoplastic Combined Chemotherapy Protocols/therapeutic use Base Sequence Brain Neoplasms/blood,genetics,immunology,pathology,therapy Cell Line, Tumor Chemokine CCL2/genetics,immunology Genes, myc/genetics Genome, Human Humans Killer Cells, Natural/immunology Neoplasm Staging Neuroblastoma/blood,genetics,immunology,pathology,therapy Proto-Oncogene Mas RNA, Neoplasm/genetics Reverse Transcriptase Polymerase Chain Reaction Transcription, Genetic
Chemicals
CCL2 protein, human Chemokine CCL2 MAS1 protein, human Proto-Oncogene Mas RNA, Neoplasm
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Metelitsa Leonid S
Department of Pediatrics, Division of Hematology-Oncology, MS #57, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027, USA.
Wu Hong-Wei
Wang Hong
Yang Yujun
Warsi Zamir
Asgharzadeh Shahab
Groshen Susan
Wilson S Brian
Seeger Robert C
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20031462
Published
2004-05-03
Pages
1213-21
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2211904
Subset
IM
Grants
NCI NIH HHS · P01 CA081403 · United States
NCI NIH HHS · CA22794 · United States
NCI NIH HHS · CA81403 · United States
External Links
PubMed source DOI: 10.1084/jem.20031462 PMC Full Text View journal details
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