Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells. V alpha 14-J alpha 15 natural killer T (NKT) cells recognize lipid antigens presented by the major histocompatibility complex class I-like protein CD1d (refs. 3,4). We have previously shown that in vivo activation of V alpha 14 NKT cells by alpha-galactosylceramide (alpha-GalCer) and CD1d potentiates Th2-mediated adaptive immune responses. Here we show that alpha-GalCer prevents development of diabetes in wild-type but not CD1d-deficient NOD mice. Disease prevention correlated with the ability of alpha-GalCer to suppress interferon-gamma but not interleukin-4 production by NKT cells, to increase serum immunoglobulin E levels, and to promote the generation of islet autoantigen-specific Th2 cells. Because alpha-GalCer recognition by NKT cells is conserved among mice and humans, these findings indicate that alpha-GalCer might be useful for therapeutic intervention in human diseases characterized by Th1-mediated pathology such as Type 1 diabetes.

Key Points GD2-specific CAR renders NKT cells cytotoxic against NB cells and results in potent in vivo antitumor activity without graft-versus-host disease. The 4-1BB-containing CAR constructs induce T helper 1–like polarization in NKT cells.

Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as pre-metastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to pre-metastatic niche formation are not fully understood. Here we demonstrate that colorectal carcinoma cells secrete VEGF-A, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in pre-metastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a pre-metastatic niche that ultimately promoted liver metastases. Importantly, pre-metastatic liver-infiltrating MDSC induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGF-A stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSC to form a pre-metastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to pre-metastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSC are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rational for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease.

Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs).