M2 macrophages express CD1d and are selectively targeted by NKT cells in tumors (127.39)

Abstract CD1d-reactive Valpha24-invariant Natural Killer T cells (NKTs) are potentially important for tumor immunity. However, the mechanism by which NKTs mediate antitumor responses against CD1d-negative tumors has remained enigmatic. Recent findings by us and others suggest that instead of attacking tumor cells directly, NKTs may target CD1d-positive tumor-supportive myelomonocytic cells. We have demonstrated that NKTs co-localize with tumor-associated macrophages (TAMs) in primary human neuroblastoma (NB). The phenotypic analysis of TAMs in primary tumors has revealed the existence of both M1- and M2-polarized subsets. However, only the numbers of CD163-positive M2 macrophages correlated with metastatic disease and poor outcome. Importantly, we found that CD1d is selectively expressed on M2, but not on M1 macrophages, both in TAMs isolated from primary NB tissues, and in in vitro polarized macrophages. NKTs mediated CD1d-dependent in vitro cytotoxicity against M2 macrophages or polarized them to an M1 phenotype via soluble mediators. The latter was in part dependent on NKT-derived GM-CSF and IFNγ. Moreover, adoptive transfer of ex-vivo expanded human NKTs resulted in a significant reduction that correlated with anti-metastatic activity. Thus, targeting of tumor-supportive M2 TAMs by NKTs reveals a novel mechanism of tumor immunity that can be exploited for the development of effective immunotherapy of solid tumors.