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CD1d-Restricted Natural Killer T Cells Can Down-regulate Tumor Immunosurveillance Independent of Interleukin-4 Receptor-Signal Transducer and Activator of Transcription 6 or Transforming Growth Factor-ß

¹ Vaccine Branch and ² Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Masaki Terabe, Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Building 10/Room 6B12, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-435-8349; Fax: 301-402-0549; E-mail: terabe{at}mail.nih.gov or Chand Khanna, Tumor and Metastasis Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9610 Medical Center Drive, Rm 315, Key West Medical Center, Rockville, MD 20850. Phone: 301-594-3406; Fax: 301-402-4422; E-mail: khannac{at}mail.nih.gov.

It has been shown previously that the suppression of tumor immunosurveillance may be a mechanism by which tumors resist immune detection and elimination. In this study, we evaluated the role of the immunoregulatory natural killer T (NKT) cells in the biology of immunosurveillance of osteosarcoma. The K7M2 mouse osteosarcoma cell line was implanted orthotopically into wild-type and NKT cell–deficient CD1d knockout (KO) BALB/c mice, and mice were monitored for growth of primary tumors. Further, we examined the role of CD4⁺ and/or CD8⁺ cells by depleting the cells in vivo and measuring CTL activity in vitro. We also asked the role of interleukin (IL)-4 receptor (IL-4R)-signal transducer and activator of transcription 6 (STAT6) signaling, including IL-13, and transforming growth factor ß (TGF-ß) by using gene-disrupted mice or treating mice with cytokine antagonists. We were surprised to find a high rate of rejection of osteosarcoma primary tumors in 88% (14 of 16) of CD1d KO mice compared with syngeneic wild-type BALB/c mice that showed rejection of tumor in <24% of mice. Further studies suggested that the rejection of tumor in CD1d KO mice was dependent on CD8⁺ lymphocytes. Distinct from other murine tumor models, the negative regulation induced by CD1d-restricted NKT cells was not dependent on IL-4R-STAT6 signaling, including IL-13, or on TGF-ß. These data suggest that a novel CD1d-restricted NKT cell–mediated mechanism for tumor immunosuppression is active in the K7M2 osteosarcoma model and that NKT cells can regulate immunosurveillance through more than one pathway. (Cancer Res 2006; 66(7): 3869-75)

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