Monday, April 15, 2019 4:08:17 PM
One adjuvant that has shown promise in preclinical studies is the use of natural killer T (NKT) cells. NKT cells display several desirable anti-tumor properties due to their ability to directly lyse tumor cells. These cells secrete both TH1 and TH2 cytokines that can modulate T cell activity and promote DC maturation through CD40L/CD40-mediated interactions [151,152,153]. Although direct anti-tumor lysis mediated by NK cells has been reported to be restricted to tumor cells that display CD1d protein on their surface [154], malignant gliomas have been shown to express CD1d. Another advantage of NKT cells is their anti-tumor immunomodulatory effect on the GBM TME. These effects range from activating immune cells such as B cells, T cells, and DCs to downregulating and killing pro-tumor TAMs and MDSCs [147,155,156,157]. Furthermore, the synergistic interaction between NKT cells and DCs leads to enhanced CD4+ and CD8+ T cell activation and has been efficacious in inducing strong and long-lasting immune responses [155,158,159,160]. In one study, the authors pulsed DCs with alpha-galactosylceramide, an NKT cell activator, and the DCs were then co-cultured with NKT cells isolated from glioma patients. The NKT cells showed robust expansion ability and functionality with a significant increase in the secretion of IFN-?. Furthermore, the expanded NKT cells demonstrated significant cytotoxic activity ex vivo against U251 glioma cells, a CD1d expressing cell line, in a Cr51 release assay compared to A172 glioma cells, a CD1d negative cell line [161]. Liu et al. also highlighted NKT cell’s efficacy as a DCV adjuvant against gliomas by using DCs pulsed with glioma-derived exosomes and a-galactosylceramide in orthotopically implanted C6 GBM cells. The authors showed an increased survival response compared to DCs pulsed with tumor lysate or with a-galactosylceramide only [147]. Thus, by optimizing the pulsed antigen for the DCs through the use of glioma-derived exosomes instead of whole tumor-lysate and the addition of an adjuvant in the form of NKT cells, Liu et al. demonstrated that combinatorial therapy can lead to synergistic cytotoxic anti-tumor activity against gliomas.
https://www.mdpi.com/2072-6694/11/4/537/htm
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