Dendritic Cell Internalization of α-Galactosylceramide from CD8 T Cells Induces Potent Antitumor CD8 T-cell Responses

Abstract

Dendritic cells (DC) present a-galactosylceramide (alpha GalCer) to invariant T-cell receptor-expressing natural killer T cells (iNKT) activating these cells to secrete a variety of cytokines, which in turn results in DC maturation and activation of other cell types, including NK cells, B cells, and conventional T cells. In this study, we showed that alpha GalCer-pulsing of antigen-activated CD8 T cells before adoptive transfer to tumor-bearing mice caused a marked increase in donor T-cell proliferation, precursor frequency, and cytotoxic lymphocyte activity. This effect was interleukin (IL)-2 dependent and involved both natural killer T cells (NKT) and DCs, as mice lacking IL-2, NKTs, and DCs lacked any enhanced response to adoptively transferred alpha GalCer-loaded CD8 T cells. iNKT activation was mediated by transfer of alpha GalCer from the cell membrane of the donor CD8 T cells onto the alpha GalCer receptor CD1d which is present on host DCs. aGalCer transfer was increased by prior activation of the donor CD8 T cells and required AP-2-mediated endocytosis by host DCs. In addition, host iNKT cell activation led to strong IL-2 synthesis, thereby increasing expansion and differentiation of donor CD8 T cells. Transfer of these cells led to improved therapeutic efficacy against established solid tumors in mice. Thus, our findings illustrate how alpha GalCer loading of CD8 T cells after antigen activation in vitro may leverage the therapeutic potential of adoptive T-cell therapies. Cancer Res; 71(24); 7442-51. (C) 2011 AACR.