Natural killer T (NKT) cells are lymphocytes with features of natural killer (NK) and of T cells placing them at the interface of innate and adaptive immunity. Like NK cells, they rapidly produce cytokines after stimulation, orienting the immune response. As T cells, they express a T cell receptor (TCR) that allows the recognition of specific lipids presented by the non-classical MHC-I molecule CD1d. There are two subsets of NKT cells, type I and type II, distinguished by their T-cell receptors. All type I NKT cells express a semi-invariant TCR (Vα24α18 in humans, Vα14Jα18 in mice) that recognizes α-galactosylceramide (α-GalCer). In contrast, type II NKT cells express a more diverse TCR repertoire. The biological activity of these two subsets of NKT cells is assessed comparing Jα18-/- mice that specifically lack type I NKT cells and in CD1d-/- mice which lack all populations of NKT cells. In tumor immunity, these two subsets of NKT cells have opposite functions. Type I NKT cells enhance and type II NKT cells suppress anti-tumor responses. It has been also reported that these two types of NKT cells cross-regulate each other. Although there is no currently identified lipid antigen recognized by all type II NKT cells, sulfatide is a relatively well-defined self-antigen recognized by a fraction of type II NKT cells. In human organs, sulfatide is rich in myelin sheath of nerve tissue and pancreas. Thus, sulfatide may release from pancreatic tissue during the invasive growth of the pancreatic cancer, and activate a fraction of type II NKT cells. To test this hypothesis, we analyzed the involvement of NKT cells in the regulation of tumor immunity in pancreatic cancer, using mouse pancreatic cancer organoid orthotropic model. The pancreatic organoids derived from KrasG12D mice were transduced with Cre and shRNA against p16, to activate Kras and repress p16, respectively. These transduced organoids were then subcutaneously injected to C57BL/6J wild type mice, and tumors were harvested after two weeks. The tumors were cut into small pieces, and the weight of each piece was measured. The piece of tumor was sewn to the pancreas of wild type, Jα18-/- mice and CD1d-/- mice. After two weeks, tumors were harvested, and the weight of tumor was measured. The tumor weight was significantly heavier in CD1d-/- mice than wild type mice (p=0.0416). Although it was not statistically significant, the tumor weight was slightly heavier in Jα18-/- mice than wild type mice. We also analyzed the population of T cell subsets in peripheral bloods, however, there were no differences among the three strains of mice. Considering these results, NKT cells may regulate tumor immunity in the microenvironment of the pancreatic cancer. Moreover, since sulfatide is rich in pancreas, sulfatide-reactive type II NKT cells may be involved in this local immune response. The detailed analysis of the regulatory functions of NKT cells in pancreas could help to develop a new immunotherapy for pancreatic cancer.
Citation Format: Shingo Kato, Tetsuya Matsuura, Yoshitaka Hippo, Atsushi Nakajima. Natural killer T cells regulate tumor immunity in mouse pancreatic cancer organoid orthotropic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4625. doi:10.1158/1538-7445.AM2017-4625