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¹ Department of Pediatrics, Division of Hematology-Oncology, Childrens Hospital Los Angeles and ² Biostatistics Core Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027
³ Cancer Immunology and AIDS Department, Dana Farber Cancer Institute, Boston, MA 02115
⁴ Children's Oncology Group, Arcadia, CA 91006

Address correspondence to Robert C. Seeger, Dept. of Pediatrics, Div. of Hematology-Oncology, MS #57, Childrens Hospital Los Angeles, 4650 Sunset Blvd., Los Angeles, CA 90027. Phone: (323) 669-5618; Fax: (323) 664-9455; email: rseeger{at}chla.usc.edu

CD1d-restricted V24-J18–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^® 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.

Key Words: lymphocytes • tumor-infiltrating • T lymphocyte subsets • cell movement • immunologic surveillance

Abbreviations used in this paper: GalCer, -galactosylceramide; DAPI, 4',6-diamidine-2'-phenylindole dihydrochloride; FU, fluorescence units; IHC, immunohistochemistry; iNKT, V24-J18–invariant natural killer T cell; TEM, transendothelial migration.

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