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

Abstract

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 + 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.

α-Galactosylceramide but Not Phenyl-Glycolipids Induced NKT Cell Anergy and IL-33–Mediated Myeloid-Derived Suppressor Cell Accumulation via Upregulation of egr2/3

“…Indeed, our findings of a-GalCer-induced expansion of immunosuppressive MDSCS in normal mice and the persistence of tumorinfiltrating MDSCs in tumor-bearing mice provided the basis for the abovementioned intriguing phenomena. In contrast, phenylglycolipids not only failed to expand MDSCs in normal mice but, in fact, markedly reduced the number of tumor infiltrating MDSCs, presumably as the result of their killing by activated NKT cells as reported previously (42). Although higher levels IL-10 and IL-13 have been reported to correlate with more MDSCs, there is no direct evidence for their causal association.…”

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

“…Pathways involving CD1d, CD40L, and NKG2D have been implicated in the regulatory effects of NKT cells on MDSC activity. 29,58,59 We show that NKT cell activation resulted in robust CD8 C T cell and NK cell mediated antitumor responses. While NKT cells can directly lyse tumor cells, this mechanism of antitumor immunity in vivo is largely associated with hematological tumors.…”

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

“…High-risk metastatic tumors frequently show amplified MYCN proto-oncogene, and overall patient survival is less than 50% (1,2). Progression of neuroblastoma is associated with expression of inflammatory factors (3), and intratumoral myeloid cells predict poor clinical outcome (4,5). A transgenic murine model resembling the aggressive growth pattern of high-risk human neuroblastoma has been characterized, where the human MYCN oncogene (TH-MYCN) drives the establishment of spontaneous tumors (6,7).…”