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-beta

Cancer Res. 2006 Apr 1;66(7):3869-75. doi: 10.1158/0008-5472.CAN-05-3421.

Abstract

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 alpha (IL-4Ralpha)-signal transducer and activator of transcription 6 (STAT6) signaling, including IL-13, and transforming growth factor beta (TGF-beta) 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-4Ralpha-STAT6 signaling, including IL-13, or on TGF-beta. 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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • 3T3 Cells
  • Animals
  • Antigens, CD1 / immunology*
  • Antigens, CD1d
  • Bone Neoplasms / immunology*
  • Down-Regulation
  • Female
  • Killer Cells, Natural / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Osteosarcoma / immunology*
  • Receptors, Interleukin-4 / immunology*
  • STAT6 Transcription Factor / immunology*
  • T-Lymphocytes, Cytotoxic / immunology
  • Transforming Growth Factor beta / immunology*

Substances

  • Antigens, CD1
  • Antigens, CD1d
  • Receptors, Interleukin-4
  • STAT6 Transcription Factor
  • Transforming Growth Factor beta