Bortezomib enhances expression of effector molecules in anti-tumor CD8+ T lymphocytes by promoting Notch-nuclear factor-κB crosstalk

Abstract

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 IFNγ secretion and expression of effector molecules, perforin and granzyme B, as well as the T-box transcription factor eomesodermin. Bortezomib also neutralized TGFβ-mediated suppression of IFNγ 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-κB (NFκB) activity by increasing the total and phosphorylated levels of the IκB kinase and IκBα as well as the cytoplasmic and nuclear levels of phosphorylated p65. Even when we blocked NFκB activity by Bay-11-7082, or NICD cleavage by γ-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-NFκB 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.

Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

“…MDSCs blocked the induction of full-length and cleaved Notch in T-cells through nitric oxide-dependent pathways (14). Also, the impaired Notch activity found in T-cells from tumor-bearing hosts was rescued by the proteasome inhibitor bortezomib, suggesting the post-translational regulation of T-cell-Notch in tumors (34). Additional data showed that methylation of the Notch regulator, Numb, triggered Notch activity upon T-cell stimulation, indicating the epigenetic regulation of Notch signaling in T-cells (35).…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…232 Thounaojam and colleagues (from Meharry Medical College, Nashville, TN, USA) found that bortezomib suppresses the growth of various solid tumors by upregulating the expression of various components of the Notch signaling pathway in lymphoid tissues including CD8 C CTLs, resulting in increased cytotoxic functions. 219,233 Guillerey and collaborators (from QIMR Berghofer Medical Research Institute, Herston, Australia) observed that anti-myeloma immune response elicited by bortezomib or cyclophosphamide critically relies on CD226, which is crucial for the effector and cytotoxic functions of NK and CD8 C T cells. 234 Finally, Wong and collaborators (from National University of Singapore, Singapore) screened a library of chemotherapeutically active platinum derivatives and characterized a Pt(II) N-heterocyclic carbene complex as a putative inducer of ICD (pending in vivo validation), based on its capacity to trigger oxidative ER stress, CALR exposure, ATP secretion, and HMGB1 release.…”

Nanosized Alumina Particle and Proteasome Inhibitor Bortezomib Prevented inflammation and Osteolysis Induced by Titanium Particle via Autophagy and NF-κB Signaling

“…The presence of titanium particles in the peri-implant region can be an obstacle for bone regeneration. At the same time BTZ has also been shown to induce NF-κB pathways in immune cells in cancer immunotherapy when used for cancer combinatorial approach, suggesting that the effect of BTZ may be cell-specific 54 . Further research is needed if we are to make further clinical use.…”