Valpha24-invariant NKT cells mediate  antitumor activity via killing  of tumor-associated macrophages.
Tumor infiltration with Valpha24-invariant NKT cells (NKTs) associates with favorable outcome in neuroblastoma and other cancers. Although NKTs can be directly cytotoxic against CD1d+ cells, the majority of human tumors are CD1d-. Therefore, the role of NKTs in cancer remains largely unknown. Here, we demonstrate that CD68+ 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.
Division of Hematology-Oncology, Department of Pediatrics, University of Southern California Keck School of Medicine, and The Saban Research Institute of Childrens Hospital Los Angeles, Los Angeles, California, USA.
Liping
L
Song
Shahab
S
Asgharzadeh
Jill
J
Salo
Kelly
K
Engell
Hong-wei
HW
Wu
Richard
R
Sposto
Tasnim
T
Ara
Ayaka M
AM
Silverman
Yves A
YA
DeClerck
Robert C
RC
Seeger
Leonid S
LS
Metelitsa
D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006017:Glycolipids / Q000378:metabolism; D006801:Humans; D007223:Infant; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D055611:Natural Killer T-Cells / Q000276:immunology*; D009362:Neoplasm Metastasis / Q000473:pathology; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D055610:Antigens, CD1d; C526877:CD1D protein, human; D006017:Glycolipids; D015850:Interleukin-6; D011948:Receptors, Antigen, T-Cell; C528689:Valpha24 protein, human