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.
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.
Terabe
Masaki
M
Vaccine Branch and Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH Bldg. 10/Rm. 6B12, 9000 Rockville Pike, Bethesda, MD 20892, USA. terabe@mail.nih.gov
Khanna
Chand
C
Bose
Seuli
S
Melchionda
Fraia
F
Mendoza
Arnulfo
A
Mackall
Crystal L
CL
Helman
Lee J
LJ
Berzofsky
Jay A
JA
D016475:3T3 Cells; D000818:Animals; D018949:Antigens, CD1 / Q000276:immunology*; D055610:Antigens, CD1d; D001859:Bone Neoplasms / Q000276:immunology*; D015536:Down-Regulation; D005260:Female; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012516:Osteosarcoma / Q000276:immunology*; D019948:Receptors, Interleukin-4 / Q000276:immunology*; D050800:STAT6 Transcription Factor / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology*
D018949:Antigens, CD1; D055610:Antigens, CD1d; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; D016212:Transforming Growth Factor beta