Bortezomib enhances antigen-specific cytotoxic T cell responses against immune-resistant cancer cells generated by STAT3-ablated dendritic cells

Kim, Jee Eun; Jin, Dong Hoon; Lee, Wang Jae; Hur, Daeyoung; Wu, T. C.; Kim, Dae-Jin

doi:10.1016/j.phrs.2013.02.001

Cited by 13 publications

(7 citation statements)

References 43 publications

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“…Most important, deletion of STAT3 in DCs did not improve the efficacy of prophylactic or therapeutic DC vaccination in the GL26 mouse tumor model. A recent publication similarly showed that STAT3 knock down in DCs elicited no improvement in in-vivo therapeutic efficacy of monotherapy vaccination in a TC-1 murine cervical cancer model when used by itself [27] . Improved survival using STAT3 knock down DC vaccination was elicited when used in combination with bortezomib treatment via a CD8 + T cell response [27] .…”

Section: Discussionmentioning

confidence: 99%

Assessing the Role of STAT3 in DC Differentiation and Autologous DC Immunotherapy in Mouse Models of GBM

et al. 2014

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Cellular microenvironments, particularly those found in tumors, elicit a tolerogenic DC phenotype which can attenuate immune responses. Central to this process is the STAT3-mediated signaling cascade. As a transcription factor and oncogene, STAT3 promotes the expression of genes which allow tumor cells to proliferate, migrate and evade apoptosis. More importantly, activation of STAT3 in tumor infiltrating immune cells has been shown to be responsible, in part, for their immune-suppressed phenotype. The ability of STAT3 to orchestrate a diverse set of immunosuppressive instructions has made it an attractive target for cancer vaccines. Using a conditional hematopoietic knockout mouse model of STAT3, we evaluated the impact of STAT3 gene ablation on the differentiation of dendritic cells from bone marrow precursors. We also assessed the impact of STAT3 deletion on phagocytosis, maturation, cytokine secretion and antigen presentation by GM-CSF derived DCs in vitro. In addition to in vitro studies, we compared the therapeutic efficacy of DC vaccination using STAT3 deficient DCs to wild type counterparts in an intracranial mouse model of GBM. Our results indicated the following pleiotropic functions of STAT3: hematopoietic cells which lacked STAT3 were unresponsive to Flt3L and failed to differentiate as DCs. In contrast, STAT3 was not required for GM-CSF induced DC differentiation as both wild type and STAT3 null bone marrow cells gave rise to similar number of DCs. STAT3 also appeared to regulate the response of GM-CSF derived DCs to CpG. STAT3 null DCs expressed high levels of MHC-II, secreted more IL-12p70, IL-10, and TNFα were better antigen presenters in vitro. Although STAT3 deficient DCs displayed an enhanced activated phenotype in culture, they elicited comparable therapeutic efficacy in vivo compared to their wild type counterparts when utilized in vaccination paradigms in mice bearing intracranial glioma tumors.

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Section: Discussionmentioning

confidence: 99%

Assessing the Role of STAT3 in DC Differentiation and Autologous DC Immunotherapy in Mouse Models of GBM

et al. 2014

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“…Bortezomib enhanced Ag-specific cytotoxic T-cell responses against immune-resistant cancer cells generated by STAT3-ablated DCs [27]. Also, bortezomib could restore MART-1 Ag expression on human melanoma cells to sensitize them to specific CTLs in vitro [28].…”

Section: Host Responsiveness To Bortezomib Treatmentmentioning

confidence: 99%

Modulatory Effects of Bortezomib on Host Immune Cell Functions

et al. 2015

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Bortezomib is an inhibitor of the ubiquitin-proteasome proteolytic pathway responsible for intracellular protein turnover. Cellular proteins controlled by this pathway represent a diverse group of potential therapeutic targets, particularly in cancer cells, which exploit this proteasomal pathway to promote their growth and diminish apoptosis. Along with inhibiting the proteasome and thus sensitizing tumor cells to apoptosis, bortezomib may also have multiple effects on the host immune responses. This review summarizes the effects that bortezomib may play on immune cell subsets in various disease states in modifying lymphocyte receptors, ligands, the expression of various cytokines and chemokines and their downstream signaling. We also propose steps that can be taken to refine combinatorial strategies that include bortezomib to improve current immunotherapeutic approaches.

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“…BTZ treatment can lead to immunogenic cell death in MM cells, resulting in uptake by, and contact-dependent activation of DC through, exposure of heat shock proteins [8]. Given that BTZ can enhance the efficacy of tumor vaccination [8,33], these findings have prompted several groups to study the effects of BTZ on functional DC development and maturation. Thus far, the majority of reports have described the effects of short-term exposure to BTZ on MoDC, an in vitro model of inflammatory DC development, and without exception, have shown deleterious effects on DC maturation, most notably through BTZ-mediated inhibition of proteasomal chymotrypsin activity [10][11][12].…”

Section: Discussionmentioning

confidence: 99%

Enhanced Dendritic Cell Development Through Long-Term Proteasome Inhibition

Ven¹,

Verbrugge

Al³

et al. 2018

J Mol Clin Med.

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Bortezomib (BTZ) is a potent and reversible proteasome inhibitor which has shown efficacy in the treatment of multiple myeloma. BTZ also affects NF-κB activity, however, the same mechanisms through which it curtails malignant cell proliferation may also compromise antitumor immunity. As dendritic cells (DC) play a vital role in the elicitation and maintenance of antitumor immunity, we herein studied the long-term effects of BTZ on human DC development and function. The CD34 + MUTZ-3 cell line, stably transduced with human telomerase reverse transcriptase (hTERT), was employed as a sustainable model to study human steady-state DC development and was grown in the presence of gradually increasing BTZ concentrations over a period of 4 months. The resultant BTZ-adapted cells were prospectively assessed for their ability to develop into mature Langerhans cells (LC). Long-term exposure to BTZ (>10 months) at a clinically relevant and apoptosis-inducing concentration (10 nM) provoked spontaneous differentiation in surviving precursors, evidenced by increased expression levels of CD14, TNF receptors and immunoproteasome subunits. Cytokine-dependent differentiation was also enhanced, resulting in increased numbers of mature DC with higher levels of co-stimulatory molecules and an increased capacity for T cell induction. Assessment of nuclear NF-κB subunit levels provided evidence for a role of canonical RelB/p50 activation in the enhanced DC differentiation and maturation established through prolonged BTZ exposure. We conclude that long-term treatment with low dose BTZ is consistent with DCdependent induction of antitumor immunity.

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Bortezomib enhances antigen-specific cytotoxic T cell responses against immune-resistant cancer cells generated by STAT3-ablated dendritic cells

Cited by 13 publications

References 43 publications

Assessing the Role of STAT3 in DC Differentiation and Autologous DC Immunotherapy in Mouse Models of GBM

Assessing the Role of STAT3 in DC Differentiation and Autologous DC Immunotherapy in Mouse Models of GBM

Modulatory Effects of Bortezomib on Host Immune Cell Functions

Enhanced Dendritic Cell Development Through Long-Term Proteasome Inhibition

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