Dendritic Cell Maturation Stage Determines Susceptibility to the Proteasome Inhibitor Bortezomib

Subklewe, Marion; Sebelin-Wulf, Kathrin; Beier, Carola; Lietz, Andreas; Mathas, Stephan; Dörken, Bernd; Pezzutto, Antonio

doi:10.1016/j.humimm.2006.12.005

Cited by 44 publications

(45 citation statements)

References 39 publications

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“…Immature monocyte-derived DC appear to be most sensitive to the effects of Bortezomib. [12][13][14] However, the data on the effect of Bortezomib on mature DC are more controversial: although our study shows that mature DC are partially resistant to proteasome inhibition, consistent with a recent study, 13 at least two other studies have shown substantial apoptosis of mature DC upon exposure to Bortezomib. 12,14 The reasons for this discrepancy is unclear, but it may have to do with the different conditions of DC maturation in the different studies.…”

Section: Discussionsupporting

confidence: 88%

“…[12][13][14] The induction of apoptosis by Bortezomib was a specific feature of cells belonging to the monocyte/DC lineage, as Bortezomib did not reduce recovery (not shown) or induce apoptosis of purified B and T lymphocytes after 24 h of culture, except at doses 450 ng/ml (Figure 2e). Similar results were obtained with purified CD34 þ progenitor cells (Figure 2e).…”

Section: Selective Depletion Of Monocytes and Dcs Following Culture Omentioning

confidence: 94%

“…9,10 There is extensive evidence that Bortezomib induces the apoptosis of in vitro monocyte-derived immature and mature DCs. [11][12][13][14] However, it is not known whether Bortezomib induces the apoptosis of 'native' DC circulating in the peripheral blood, although it may alter the function of circulating myeloid DC ex vivo. 15 Moreover, the effects of Bortezomib on monocytes have not been thoroughly investigated.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade)

Arpinati

Chirumbolo

Nicolini

et al. 2008

Bone Marrow Transplant

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Section: Discussionsupporting

confidence: 88%

Section: Selective Depletion Of Monocytes and Dcs Following Culture Omentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade)

Arpinati

Chirumbolo

Nicolini

et al. 2008

Bone Marrow Transplant

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“…5A). Prior studies have shown that bortezomib can indirectly reduce T cell alloreactivity by inhibiting dendritic cell (DC) maturation, phagocytosis, and IL-12 production and can directly suppress allogeneic T cell proliferation and Th1 responses (12)(13)(14)(15)(16)(17). In contrast, the reduction in T cell immunity against tumor cells observed in our studies occurred as a direct effect of bortezomib on tumor cells because tumors were extensively washed precluding bortezomibinduced suppression of effector cells.…”

Section: Resultscontrasting

confidence: 60%

Cutting Edge: Bortezomib-Treated Tumors Sensitized to NK Cell Apoptosis Paradoxically Acquire Resistance to Antigen-Specific T Cells

Lundqvist

Rao

et al. 2009

The Journal of Immunology

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Bortezomib augments caspase-8 activity, rendering tumors susceptible to NK cell lysis. We hypothesized this effect would likewise sensitize tumors to Ag-specific CTLs. Instead, bortezomib-treated tumors that acquired sensitivity to NK cells simultaneously became resistant to killing by Ag-specific CTLs. Reduction in CTL killing persisted for days, was not due to changes in tumor expression of MHC class I, and was overcome by pulsing tumors with peptides recognized by tumor-reactive CTLs. Tumor-outgrowth experiments showed tumors grew faster in SCID mice when cocultures of tumor-reactive CTLs and bortezomib-treated tumors were injected compared with untreated tumors (tumor doubling time 3.1 and 10.6 d, respectively; p < 0.01), whereas tumors grew slower in mice receiving cocultures of NK cells and bortezomib-treated tumors compared with untreated tumors (11.8 d and 5.0 d, respectively; p < 0.01). These findings demonstrate bortezomib-treated tumors sensitized to NK cell apoptosis paradoxically acquire resistance to CTLs as a consequence of bortezomib altering proteasomal processing and presentation of tumor Ags.

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“…It has been reported that bortezomib adversely affects monocyte-derived DCs by inhibiting proteasomal b5 subunit-located chymotrypsin-like peptidase, which is part of the ubiquitin-proteasome pathway that is crucial for the preservation of normal DC processes (43). Additional reports of unfavorable effects that bortezomib has on DCs include the reduction of monocyte-derived DC phagocytic activity (44) and the triggering of monocyte-derived DC apoptosis (45) with differentially greater apoptotic effect on immature than mature monocyte-derived DCs (46). It is also a concern that bortezomib may cause immunosuppression by inhibiting the action and/or proliferation of T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Immune Mechanism of the Antitumor Effects Generated by Bortezomib

Chang

Hsu

et al. 2012

The Journal of Immunology

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Bortezomib, a proteasome inhibitor, is a chemotherapeutic drug that is commonly used to treat a variety of human cancers. The antitumor effects of bortezomib-induced tumor cell immunogenicity have not been fully delineated. In this study, we examined the generation of immune-mediated antitumor effects in response to treatment by bortezomib in a murine ovarian tumor model. We observed that tumor-bearing mice that were treated with bortezomib had CD8+ T cell-mediated inhibition of tumor growth. Furthermore, the comparison of tumor cell-based vaccines that were produced from tumor cells treated or untreated with bortezomib showed vaccination with drug-treated tumor cell-based vaccines elicited potent tumor-specific CD8+ T cell immune response with improved therapeutic antitumor effect in tumor-bearing mice. Conversely, the untreated tumor cell-based vaccines led to no appreciable antitumor response. Treatment of tumor cells with bortezomib led to the upregulation of Hsp60 and Hsp90 on the cell surface and promoted their phagocytosis by dendritic cells (DCs). However, cell surface expression of Hsp60, instead of Hsp90, is the more important determinant of whether bortezomib-treated tumor cells can generate tumor-specific CD8+ T cells. CD11c+ DCs that were treated with bortezomib in vitro had enhanced phagocytic activities. In addition, CD11c+ DCs from bortezomib-treated tumor-bearing mice had increased maturation. At lower concentrations, bortezomib had no inhibitory effects on T cell proliferation. Taken together, our data indicate that bortezomib can render tumor cells immunogenic by upregulating the cell surface expression of heat shock protein 60 and heat shock protein 90, as well as improve DC function, which results in potent immune-mediated antitumor effects.

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Dendritic Cell Maturation Stage Determines Susceptibility to the Proteasome Inhibitor Bortezomib

Cited by 44 publications

References 39 publications

Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade)

Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade)

Cutting Edge: Bortezomib-Treated Tumors Sensitized to NK Cell Apoptosis Paradoxically Acquire Resistance to Antigen-Specific T Cells

Immune Mechanism of the Antitumor Effects Generated by Bortezomib

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