Bortezomib impacts Notch—miR-155 mediated augmentation of CD8+T Cell antitumor immunity

Abstract

Abstract The immunosuppressive tumor microenvironment dampens host antitumor immunity by multiple mechanisms including interference with the Notch system, which is important for various cell fate decisions and hematopoietic cell differentiation and function. We observed that treatment with bortezomib, a proteasome inhibitor, in mice bearing subcutaneous tumors resulted in an upregulated expression of various Notch signaling components in lymphoid tissues and increased CD8+T lymphocyte IFNγ secretion and expression of effector molecules, perforin and granzyme-B, as well as the T-box transcription factor eomesodermin. Of note, bortezomib reversed tumor-induced downregulation of Notch receptors, Notch1 and Notch2, as well as increased the levels of cleaved Notch intracellular domain (NICD) and downstream targets Hes1 and Hey1 in tumor-draining CD8+T cells. These data suggest that bortezomib can reverse tumor-induced dysfunction of CD8+T cells by its intrinsic stimulatory effects. Our preliminary data also suggest that bortezomib can positively regulate miR-155 expression in CD8+ T cells from mice bearing tumor. Further, miR-155 suppression was found to downregulate bortezomib-induced increase in Notch target genes in T cells. We are currently elucidating how bortezomib affects the expression of miR-155 and its target genes, such as suppressor of cytokine signaling 1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP1) that are associated with T cell function. These data provide novel insights on using bortezomib not only as an agent to sensitize tumors to cell death, but also to provide lymphocyte-stimulatory effects, thereby overcoming immunosuppressive actions of tumor on antitumor T cell functions.