THE ROLES OF CHEMOKINES, CHEMOKINE RECEPTORS AND GLYCOLIPID ACTIVATION IN NKT CELL TUMOUR INFILTRATION

Abstract

Higher levels of NKT cell infiltration correlate with improved prognosis in many human cancers. Therefore, we sought to identify factors which contribute to this process. We identified three chemokine receptors, CXCR3, CXCR6, and CCR5, which mediate NKT cell tumour homing. In competitive homing experiments, wild type (WT) NKT cells homed more efficiently to tumours than CCR5-/-, CXCR3-/- or CXCR6-/- NKT cells. We also demonstrated that combined intratumoural administration of a CXCR3 ligand (CXCL10) and an NKT cell activating glycolipid (-GalCer) significantly enhanced NKT cell recruitment and reduced tumour growth. In contrast, treatment with CXCL16 (CXCR6 ligand) increased tumour size. As CCR5 has been suggested to regulate NKT cell activity, we compared expansion and cytokine production from WT and CCR5-/- NKT cells, identifying reduced serum levels of IL-4 in CCR5-/- mice following NKT cell stimulation. Our results demonstrate that co-treatment of tumours with exogenous chemokines and NKT cell-activating glycolipids represents a novel strategy for therapeutic development.