Vα24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages

• Published in: The Journal of clinical investigation Vol. 119; no. 6; pp. 1524 - 1536
• Main Authors: Song, Liping, Asgharzadeh, Shahab, Salo, Jill, Engell, Kelly, Wu, Hong-wei, Sposto, Richard, Ara, Tasnim, Silverman, Ayaka M, DeClerck, Yves A, Seeger, Robert C, Metelitsa, Leonid S
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01.06.2009
• Subjects: Immune response; Killer cells; Macrophages; Physiological aspects; Prevention; Tumors; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci37869

Tumor infiltration with Vα24-invariant NKT cells (NKTs) associates with favorable outcome in neuroblastoma and other cancers. Although NKTs can be directly cytotoxic against [CD1d.sup.+] cells, the majority of human tumors are [CD1d.sup.-]. Therefore, the role of NKTs in cancer remains largely unknown. Here, we demonstrate that [CD68.sup.+] tumor-associated monocytes/macrophages (TAMs) represented the majority of CD1d-expressing cells in primary human neuroblastomas. TAMs stimulated neuroblastoma growth in human cell lines and their xenografts in NOD/SCID mice via IL-6 production. Indeed, TAMs produced IL-6 in primary tumors and in the BM of patients with metastatic neuroblastoma. Gene expression analysis using TaqMan low-density arrays of 129 primary human neuroblastomas without MYCN amplification revealed that high-level expression of TAM-specific genes (CD14, CD16, IL6, IL6R, and TGFB1) 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 of monocytes was CD1d restricted because it was inhibited by a CD1d-specific mAb. Cotransfer of human monocytes and NKTs to tumor-bearing NOD/SCID mice decreased monocyte number at the tumor site and suppressed tumor growth compared with mice transferred with monocytes alone. Thus, killing of TAMs reveals what we believe to be a novel mechanism of NKT antitumor activity that relates to the disease outcome.