Various immunosuppressive cells, such as Tregs and type II NKT cells, mediate the immune regulation of cancer. Many studies have demonstrated the importance of regulatory cells; however, it is still not clear why different suppressive cells play a dominant role in different models. Here, we examined the relative role of two suppressors - Tregs and type II NKT cells – in a subcutaneous CT26 tumor model in three strains of mice: wild-type, NKT cell-deficient CD1dKO mice and Jα18KO, which lack type I NKT cells but still retain type II NKT cells. Tumors grew in all three strains, but Treg blockade by anti-CD25 mAb (PC61) led to tumor rejection in WT and CD1dKO but not in Jα18KO mice, suggesting that in Jα18KO mice, Tregs are not necessary for immune suppression. We hypothesized that cross regulation between type I and type II NKT cells in wild-type mice leaves Treg cells as primary suppressors, whereas in mice lacking type I NKT cells, unopposed type II NKT cells can suppress tumor immunity even when Tregs are blocked. We confirmed this hypothesis in PC61-treated Jα18KO mice by blocking type II NKT cells using anti-CD1d mAb (1B1) or by adoptive transfer of type I NKT cells combined with Treg blockade. These results support our hypothesis that it is necessary to block both suppressors, type II NKT cells and Tregs, in order to achieve protection. Also, activation of type II NKT cells by sulfatide in PC61-treated wild-type mice abrogated the protective effect of Treg blockade, indicating that shifting the balance between the two types of NKT cells toward immunosuppressive type II NKT cell dominance suppresses tumor immunity even in the absence of Tregs. We conclude that both Tregs and type II NKT cells can concurrently suppress tumor immunity and the balance between these is controlled in part by a third T cell, the type I NKT cell, regulating the regulators. Finally as cancer patients often have deficient type I NKT cell function somewhat like the Jα18KO mice, managing this delicate balance among three T cells may be critical for the success of immunotherapy of human cancer.

Citation Format: Liat Izhak, Elena Ambrosino, Jessica J. O'Konek, Shingo Kato, Stanley T. Parish, Zheng Xia, David Venzon, Jay A. Berzofsky, Masaki Terabe. Delicate balance among three types of T cells in concurrent regulation of tumor immunity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 460. doi:10.1158/1538-7445.AM2013-460