Regulation of invariant natural killer T cell anti-tumor responses by the adaptor molecule Signaling Lymphocytic Activation Molecule-associated protein (SAP). (162.47)

Abstract

Abstract Invariant natural killer T (iNKT) cells comprise a unique sub-lineage of innate-like T lymphocytes that participate in anti-tumor immune surveillance. However, several questions remain regarding the mechanisms by which these cells mediate killing of tumor cells. We observe that primary murine iNKT cell cytotoxicity against tumor cells is T cell receptor (TCR)-dependent and requires target cell presentation of iNKT cell-directed agonistic lipid antigens. Interestingly, expression of the cytoplasmic adaptor molecule SAP in primary murine iNKT cells is required for optimal TCR-mediated iNKT cell cytolytic responses towards B- and T-leukemia cells in vitro as well as iNKT cell-mediated control of leukemia cell growth in mice lacking CD8+ T and NK cells. iNKT cell cytotoxicity relies on expression of the Src family tyrosine kinase Fyn, a known SAP binding protein, and on the engagement of SLAM family receptors on iNKT and target cells. Of note, SAP- or Fyn- silenced human iNKT cells exhibit significantly impaired killing of T-leukemia cells in vitro, suggesting that SAP-associated signals are also critical for human iNKT cell anti-tumor cytotoxicity. These studies provide the first mechanistic insights into the signaling mechanisms underlying TCR-induced iNKT cell killing of tumor cells. Studies are ongoing to further elucidate the specific SLAM receptor(s) and downstream signaling mechanisms by which SAP regulates murine and human iNKT cell anti-tumor responses.