The
glycosphingolipid α-
galactosylceramide (α-GalCer) is a well-described immune activator with strong anti-
tumor properties in animal models. It is presented on CD1d and acts by stimulating the invariant, type I, natural killer T (iNKT) lymphocytes to rapidly secrete TH1 and TH2 associated
cytokines. This in turn promotes activation of a diversity of immune cells including natural killer (NK) cells with anti-
tumor functions. Prior to
tumor development, iNKT cells can also perform
tumor surveillance and naturally protect from emergence of
cancer. In contrast, we have recently demonstrated that iNKT cells naturally promote
polyps in the spontaneous murine
adenomatous polyposis coli (Apc) ApcMin/+ model for
colon cancer, associated with suppressed TH1 immunity and enhanced immunoregulation. Here we investigated whether iNKT cell directed
immunotherapy could subvert the
polyp promoting function of iNKT cells and reduce
polyp growth in this model. We treated ApcMin/+ mice with α-GalCer, or synthetic derivatives of this
ligand (
C-glycoside and C20:2) that have enhanced immunoregulatory properties. Treatment with iNKT cell
ligands led to increased iNKT cell division, but reduced iNKT cell frequencies, lower NK1.1 expression and elevation of PD-1. ApcMin/+ mice that had been treated either long-term (5-15 weeks of age), or short-term (12-15 weeks of age) with α-GalCer demonstrated a significant decrease in
polyp burden. Surprisingly, long-term treatment with the TH1 biasing
ligand C-glycoside did not have significant effects on
polyps, while long-term treatment with the TH2 biasing
ligand C20:2 enhanced
polyp growth. In stark contrast, short-term treatment with C20:2 led to reduction in
polyp numbers and size. Reduced
polyp burden after long-term treatment was associated with increased expression of genes indicating a pro-inflammatory
polyp microenvironment.
Polyp-reducing short-term treatment led to CD8 T cell activation specifically in
polyps, and decreased
tumor infiltrating and splenic macrophages, and a switch toward a pro-inflammatory phenotype. Thus, iNKT cell directed
therapy could subvert the natural
polyp enhancing function of iNKT cells, overcome immunosuppression, and reduce
polyps. However, different iNKT cell activating
ligands had opposite effects, and the timing of treatment had a major influence on outcomes.