Bortezomib enhances expression of effector molecules in antitumor CD8(+) T lymphocytes by promoting Notch-nuclear factor.B crosstalk

作者：Thounaojam Menaka C; Dudimah Duafalia F; Pellom Samuel T Jr; Uzhachenko Roman V; Carbone David P; Dikov Mikhail M; Shanker Anil^*

来源：Oncotarget, 2015, 6(32): 32439-32455.

DOI：10.18632/oncotarget.5857

• Notch signaling
• NF-kappa B
• cancer immunosuppression
• T cell lmmunotherapy
• proteasome inhibition

The immunosuppressive tumor microenvironment usurps host antitumor immunity by multiple mechanisms including interference with the Notch system, which is important for various metazoan cell fate decisions and hematopoietic cell differentiation and function. We observed that treatment with the proteasome inhibitor bortezomib in mice bearing various solid tumors resulted in an upregulated expression of various Notch signaling components in lymphoid tissues, thereby increasing CD8(+)T-lymphocyte IFN gamma secretion and expression of effector molecules, perforin and granzyme B, as well as the T-box transcription factor eomesodermin. Bortezomib also neutralized TGF beta-mediated suppression of IFN gamma and granzyme B expression in activated CD8(+)T-cells. 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. Moreover, bortezomib promoted CD8(+)T-cell nuclear factor-kappa B (NF kappa B) activity by increasing the total and phosphorylated levels of the I kappa B kinase and I kappa B alpha as well as the cytoplasmic and nuclear levels of phosphorylated p65. Even when we blocked NF kappa B activity by Bay-11-7082, or NICD cleavage by gamma-secretase inhibitor, bortezomib significantly increased expression of Notch Hes1 and Hey1 genes as well as perforin, granzyme B and eomesodermin in activated CD8(+)T-cells. Data suggest that bortezomib can rescue tumor-induced dysfunction of CD8(+)T-cells by its intrinsic stimulatory effects promoting NICD-NF kappa B crosstalk. These findings 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 anti-tumor T-cell functions.

• 出版日期2015-10-20