The role of PI3K in modulating NKT cell responses to Mantle Cell Lymphoma

Abstract

Abstract Natural Killer T (NKT) cells are important in the initiation and regulation of immune responses to cancers. The observation that mantle cell lymphoma (MCL) patients have a significant reduction in both NKT cell number and function suggests that the antitumor effects mediated by these cells may be compromised. MCL is characterized by the chromosomal translocation and nuclear overexpression of Cyclin D1. Secondary chromosomal abnormalities and dysregulation of cell cycle machinery also contribute to MCL pathogenesis, such as aberrant or constitutive activation of phosphatidylinositol 3 kinase (PI3K). We hypothesize that constitutive activation of PI3K in MCL alters the repertoire of lipids in these cells, ultimately resulting in decreased CD1d-mediated NKT responses to MCL. In this study, we used small molecule pharmacologic inhibitors of PI3K (PI3Ki) to investigate the role of PI3K signaling on MCL survival and immunogenicity both in vitro and in vivo. Treatment with PI3Ki induced apoptosis in human MCL cell lines and enhanced their immunogenicity. In addition, we have found that treatment of peripheral blood mononuclear cells with isoform-specific PI3Ki does not suppress T cell activation; whereas, treatment with a pan PI3Ki, BEZ-235, completely abrogates NKT/T cell responses. These studies suggest inhibitors targeting individual isoforms may have higher therapeutic efficacy. Collectively, this work will advance our understanding of differences in the modes of PI3K signaling in MCL survival and in antigen processing and presentation.