Natural Killer T (NKT) cells mediate anti-tumor activity via killing of tumor-associated macrophages (40.19)

Abstract

Abstract Tumor infiltration with CD1d-reactive Vα24-invariant NKT cells associates with favorable outcome in neuroblastoma and other cancers. However, the function of NKTs in tumor immunity remains largely unknown. We demonstrate that CD68+ tumor-associated monocytes/macrophages (TAMs) represent the majority of CD1d-expressing cells in primary neuroblastomas. TAMs in vitro and in vivo stimulated neuroblastoma growth via IL-6 production and were the source of IL-6 in primary tumors and metastatic bone marrows in patients. Gene expression analysis with TaqMan® low-density arrays of 129 primary MYCN non-amplified neuroblastomas revealed that high level expression of TAM genes (CD14, CD16, IL-6, IL-6R, and TGFβ) was associated with poor 5-year event-free survival. While NKTs were not cytotoxic against neuroblastoma cells, they effectively killed monocytes pulsed with tumor cell lysate. The killing was CD1d-restricted since it was inhibited by anti-CD1d mAb. Co-transfer of human monocytes and NKTs to tumor-bearing NOD/SCID mice decreased monocyte number at the tumor site and delayed tumor growth compared to mice transferred with monocytes alone. Thus, killing of TAMs reveals a novel mechanism of NKT cell anti-tumor activity that relates to the disease outcome and should be considered for NKT-based therapeutic strategies. Supported by NIH grants: RO1 CA116548 (LSM) and PO1 CA81403 (RCS).