Despite the progress in understanding tumor immunosurveillance and advances in tumor immunotherapy, therapeutic immunity to cancer is still not an established modality of treatment. One of the reasons for the failure of antitumor immune response is the existence of mechanisms for tumor tolerance. In this context, different T cell subsets with suppressive function have been described, as the widely studied CD4+CD25+ T regulatory (Treg) cell. Another cell reported to suppress anti-tumor immune responses is the CD1d-restricted natural killer (NK) T cell. Our laboratory previously demonstrated the role of suppressive CD4+ CD1d-dependent CD4+ NKT cells both in an immunogenic regressor tumor model and in a nontransfected, nonregressor, syngeneic tumor model, the lung metastases of the CT26 colon carcinoma. The existence of suppressive NKT cells in the CT26 tumor model is confirmed by the observation that both CD4+ T cell-depleted mice and CD1d KO mice, which lack CD1d-restricted NKT cells, were significantly resistant to lung metastases. In the same tumor model, we have now excluded an additional suppressive role of the Treg cell, as the depletion of Treg cells did not protect the mice from tumor growth. We then investigated whether the regulatory NKT cell is the better characterized Vα14-Jα18+ (type I) NKT cell, whose activation has been shown to be beneficial in a number of tumor models, or is the different and less well characterized non-Vα14-Jα18+ (type II) NKT cell. Although CD1d KO mice were significantly protected from tumor growth, Jα18 KO mice, which lack the type I NKT cell, were not. Moreover, like NKT cell-intact wild type mice, but unlike CD1d KO mice, Jα18 KO mice do not have any tumor antigen-specific lytic activity in vivo. These results indicate that type II NKT cells, in the absence of type I NKT cells, are sufficient for the down regulation of the immunosurveillance and the cytotoxic immune response against the CT26 tumor. Taken together all the observations suggest that the immunosuppressive CD4+ NKT cell is the type II NKT cell. As confirmation of this conclusion, CD4+ T cell-depleted Jα18 KO mice were protected from tumor growth. Finally, these findings may distinguish the different roles of these two NKT cell subsets in the regulation of tumor immunity and resolve an apparent paradox regarding the function of NKT cells in tumor immunology.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]