Dendritic cells loaded with myeloma cells pretreated with a combination of JSI-124 and bortezomib generate potent myeloma-specific cytotoxic T lymphocytes in vitro

Jung, Sung‐Hoon; Lee, Youn-Kyung; Lee, Hyunju; Choi, Nu-Ri; Vo, Manh-Cuong; Hoang, My-Dung; Lim, Mi-Seon; Nguyen-Pham, Thanh-Nhan; Kim, Hyeoung-Joon; Lee, Je‐Jung

doi:10.1016/j.exphem.2013.12.008

Cited by 18 publications

(15 citation statements)

References 25 publications

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“…Lack of specific hallmark of cancer is reason for using of whole tumor cells (tumor apoptotic bodies, tumor cell lysates, or tumor cell-derived RNA), which represent full characteristics of tumor identity, as common source of tumor antigens in clinical trials of dendritic cell (DC) based cancer vaccines [ 1 , 2 ]. Among these antigen preparation procedures, ultraviolet B (UVB) irradiation is a safe, inexpensive, and easy method of inducing a mixed population of viable, early apoptotic, and late apoptotic/necrotic cells with various proportions during tumor antigen preparation [ 3 , 4 ]. However, the immunogenic properties of prepared tumor antigens depend on the cell death stage.…”

Section: Introductionmentioning

confidence: 99%

Branched Polyethylenimine-Superparamagnetic Iron Oxide Nanoparticles (bPEI-SPIONs) Improve the Immunogenicity of Tumor Antigens and Enhance Th1 Polarization of Dendritic Cells

Hoang

Lee

et al. 2015

Journal of Immunology Research

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Nanoparticles in the field of dendritic cell (DC) research are emerging as a promising method of enhancing the efficacy of cancer immunotherapy. We investigated the effect of branched polyethylenimine-superparamagnetic iron oxide nanoparticles (bPEI-SPIONs) on tumor cells loaded onto DCs. The tumor antigens were prepared as follows: (1) apoptotic U266 cells with ultraviolet B (UVB) irradiation followed by a 2 h incubation in the absence (2 h postirradiated cells) or (2) presence of bPEI-SPIONs (bPEI-SPION 2 h postirradiated cells) and (3) apoptotic U266 cells with UVB irradiation followed by an overnight 16 h incubation (16 h postirradiated cells). bPEI-SPIONs render U266 cells sensitive to UVB irradiation through reactive oxygen species production to accelerate apoptotic death. The 2 h postirradiated cells and bPEI-SPION 2 h postirradiated cells released immunogenic proteins, including Hsp70, Hsp90, and HMGB1. The DCs loaded with bPEI-SPION 2 h postirradiated cells showed the highest IL-12p70 production and Th1 polarization compared with other DCs. These results suggest that bPEI-SPIONs are a promising method of enhancing the immunogenicity of tumor cells and promoting Th1 polarization of DCs loaded with these tumor cells.

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Section: Introductionmentioning

confidence: 99%

Branched Polyethylenimine-Superparamagnetic Iron Oxide Nanoparticles (bPEI-SPIONs) Improve the Immunogenicity of Tumor Antigens and Enhance Th1 Polarization of Dendritic Cells

Hoang

Lee

et al. 2015

Journal of Immunology Research

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“…It was also shown that chaetocin produces minimal toxicity at concentrations necessary for peak induction [ 42 ]. Similarly, our previous study observed that the pretreatment of myeloma cells with JSI-124 and bortezomib can recover DC functions through the up-regulation of HSP90 and down-regulation of p-STAT3 and inhibitory cytokines, and that these DCs can potently generate myeloma-specific CTLs [ 15 ]. Therefore, we speculated that the induction of dying myeloma cells with the HMT inhibitor chaetocin acted to potentiate the expression of CTA and HSP90 on the surface of dying tumor cells.…”

Section: Discussionmentioning

confidence: 71%

Chaetocin enhances dendritic cell function via the induction of heat shock protein and cancer testis antigens in myeloma cells

Nguyen-Pham

Lee

et al. 2017

Oncotarget

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Dendritic cells (DC)-based vaccines are considered useful in cancer immuno-therapy, and the interactions of DC and dying tumor cells are important and promising for cancer immunotherapy. We investigated whether chaetocin could be used to induce death of myeloma cells, for loading onto DCs can affect DCs function. In this study, we show that the dying myeloma cells treated with chaetocin resulted in the induction of heat shock protein (HSP) 90, which was inhibited by antioxidant N-acetyl cysteine, and showed an increase in the expression of MAGE-A3 and MAGE-C1/CT7. DCs loaded with chaetocin-treated dying myeloma cells produced low levels of IL-10 and enhanced the cross presentation of DCs. Additionally, these DCs most potently inhibited regulatory T cells, induced Th1 polarization and activated myeloma-specific cytotoxic T lymphocytes compared with DCs loaded with UVB-irradiated dying myeloma cells. These results suggest that the pretreatment of myeloma cells with chaetocin can enhance DC function through the up-regulation of HSP90 and cancer testis antigens in dying myeloma cells and can potently induce the Th1 polarization of DCs and myeloma-specific cytotoxic T lymphocytes.

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“…64 This notion is supported by recent studies suggesting that myeloma patients may develop HSPdirected T-cell immune responses. 44,65 Despite the fact that all of our patients have been treated with inducers of immunogenic cell death prior to serum antibody analysis, only those who underwent allogeneic HSCT (but not those at first diagnosis, after induction or after autologous HSCT) show a high frequency of anti-HSP or antimyeloma B-cell immune responses. One potential explanation for the more B-cell permissive immune environments after allogeneic HSCT could be related to T-cell exhaustion in the context of myeloma and autologous HSCT because B cells need T-cell help in the majority of responses.…”

Section: Discussionmentioning

confidence: 99%

A transplant “immunome” screening platform defines a targetable epitope fingerprint of multiple myeloma

Schieferdecker

Oberle

Thiele

et al. 2016

Blood

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Key Points• The myeloma transplant B-cell immunome is predictive for response to treatment.• It may be exploited by immunosequencing and library technology as a source for unique target structures and antibodies for immunotherapy.Multiple myeloma (MM) is a hematological cancer for which immune-based treatments are currently in development. Many of these rely on the identification of highly diseasespecific, strongly and stably expressed antigens. Here, we profiled the myeloma B-cell immunome both to explore its predictive role in the context of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and to identify novel immunotherapeutic targets. We used random peptide phage display, reverse immunization, and nextgeneration sequencing-assisted antibody phage display to establish a highly myelomaspecific epitope fingerprint targeted by B-cell responses of 18 patients in clinical remission. We found that allogeneic HSCT more efficiently allowed production of myeloma-specific antibodies compared with autologous HSCT and that a highly reactive epitope recognition signature correlated with superior response to treatment. Next, we performed myeloma cell surface screenings of phage-displayed patient transplant immunomes. Although some of the screenings yielded clear-cut surface binders, the majority of screenings did not, suggesting that many of the targeted antigens may in fact not be accessible to the B-cell immune system in untreated myeloma cells. This fit well with the identification of heat-shock proteins as a class of antigens that showed overall the broadest reactivity with myeloma patient sera after allogeneic HSCT and that may be significantly translocated to the cell surface upon treatment as a result of immunogenic cell death. Our data reveal a disease-specific epitope signature of MM that is predictive for response to treatment. Mining of transplant immunomes for strong myeloma surface binders may open up avenues for myeloma immunotherapy. (Blood. 2016;127(25):3202-3214)

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Dendritic cells loaded with myeloma cells pretreated with a combination of JSI-124 and bortezomib generate potent myeloma-specific cytotoxic T lymphocytes in vitro

Cited by 18 publications

References 25 publications

Branched Polyethylenimine-Superparamagnetic Iron Oxide Nanoparticles (bPEI-SPIONs) Improve the Immunogenicity of Tumor Antigens and Enhance Th1 Polarization of Dendritic Cells

Branched Polyethylenimine-Superparamagnetic Iron Oxide Nanoparticles (bPEI-SPIONs) Improve the Immunogenicity of Tumor Antigens and Enhance Th1 Polarization of Dendritic Cells

Chaetocin enhances dendritic cell function via the induction of heat shock protein and cancer testis antigens in myeloma cells

A transplant “immunome” screening platform defines a targetable epitope fingerprint of multiple myeloma

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