Generation of Mouse Pluripotent Stem Cell–Derived Proliferating Myeloid Cells as an Unlimited Source of Functional Antigen-Presenting Cells

Zhang, Rong; Liu, Tian Yi; Senju, Satoru; Haruta, Miwa; Hirosawa, Narumi; Suzuki, Motoharu; Tatsumi, Minako; Maki, Hiroyuki; Nakatsuka, Ryusuke; Matsuoka, Yoshikazu; Sasaki, Yutaka; Tsuzuki, Shinobu; Nakanishi, Hayao; Araki, Ryoko; Abe, Masumi; Akatsuka, Yoshiki; Sakamoto, Yasushi; Sonoda, Yoshiaki; Nishimura, Yasuharu; Kuzushima, Kiyotaka; Uemura, Yukari

doi:10.1158/2326-6066.cir-14-0117

Cited by 18 publications

(35 citation statements)

References 47 publications

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“…Therefore, ex vivo DC manufacturing has an immediate biotechnological application. DC generation from PSCs is a promising approach; however, PSC-derived DCs often exhibited a suboptimal T cell-activation capacity (6,11,13). Consistent with this notion, in this study we found that ES cell-derived DCs represented less mature cells compared with adult stem cell-derived DCs.…”

supporting

confidence: 86%

“…In this study, we examined the transcription factor network in stem cell-derived differentiated immune cells. GM-CSF-dependent dendritic cell (DC) development was selected as a differentiation model because this cell type can be generated from adult stem cells and ES cells (6)(7)(8)(9)(10)(11)(12)(13). Moreover, numerous transcription factors were described that control the commitment and specification of DCs (14,15).…”

mentioning

confidence: 99%

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Immunogenic Dendritic Cell Generation from Pluripotent Stem Cells by Ectopic Expression of Runx3

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Simo

et al. 2017

The Journal of Immunology

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Application of dendritic cells (DCs) to prime responses to tumor Ags provides a promising approach to immunotherapy. However, only a limited number of DCs can be manufactured from adult precursors. In contrast, pluripotent embryonic stem (ES) cells represent an inexhaustible source for DC production, although it remains a major challenge to steer directional differentiation because ES cell-derived cells are typically immature with impaired functional capacity. Consistent with this notion, we found that mouse ES cell-derived DCs (ES-DCs) represented less mature cells compared with bone marrow-derived DCs. This finding prompted us to compare the gene expression profile of the ES cell- and adult progenitor-derived, GM-CSF-instructed, nonconventional DC subsets. We quantified the mRNA level of 17 DC-specific transcription factors and observed that 3 transcriptional regulators (Irf4, Spi-B, and Runx3) showed lower expression in ES-DCs than in bone marrow-derived DCs. In light of this altered gene expression, we probed the effects of these transcription factors in developing mouse ES-DCs with an isogenic expression screen. Our analysis revealed that forced expression of Irf4 repressed ES-DC development, whereas, in contrast, Runx3 improved the ES-DC maturation capacity. Moreover, LPS-treated and Runx3-activated ES-DCs exhibited enhanced T cell activation and migratory potential. In summary, we found that ex vivo-generated ES-DCs had a compromised maturation ability and immunogenicity. However, ectopic expression of Runx3 enhances cytokine-driven ES-DC development and acts as an instructive tool for the generation of mature DCs with enhanced immunogenicity from pluripotent stem cells.

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confidence: 86%

mentioning

confidence: 99%

Immunogenic Dendritic Cell Generation from Pluripotent Stem Cells by Ectopic Expression of Runx3

Takács

Botó

Simo

et al. 2017

The Journal of Immunology

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“…21 Measurement of cytokines Cytokine levels in culture supernatants were measured using enzyme-linked immunosorbent assays (hIFN-γ, hIL-4, hIL-10, hIL-17 and hIL-12p70; eBioscience). 21 51 Cr release assay Cytotoxic activity was measured using the standard 51 Cr release assay, as described.…”

Section: Cell Proliferationmentioning

confidence: 99%

BCR–ABL-specific CD4+ T-helper cells promote the priming of antigen-specific cytotoxic T cells via dendritic cells

et al. 2016

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The advent of tyrosine kinase inhibitor (TKI) therapy markedly improved the outcome of patients with chronic-phase chronic myeloid leukemia (CML). However, the poor prognosis of patients with advanced-phase CML and the lifelong dependency on TKIs are remaining challenges; therefore, an effective therapeutic has been sought. The BCR-ABL p210 fusion protein's junction region represents a leukemia-specific neoantigen and is thus an attractive target for antigen-specific T-cell immunotherapy. BCR-ABL p210 fusion-region-specific CD4 T-helper (Th) cells possess antileukemic potential, but their function remains unclear. In this study, we established a BCR-ABL p210 b3a2 fusion-region-specific CD4 Th-cell clone (b3a2-specific Th clone) and examined its dendritic cell (DC)-mediated antileukemic potential. The b3a2-specific Th clone recognized the b3a2 peptide in the context of HLA-DRB1*09:01 and exhibited a Th1 profile. Activation of this clone through T-cell antigen receptor stimulation triggered DC maturation, as indicated by upregulated production of CD86 and IL-12p70 by DCs, which depended on CD40 ligation by CD40L expressed on b3a2-specific Th cells. Moreover, in the presence of HLA-A*24:02-restricted Wilms tumor 1 (WT1) peptide, DCs conditioned by b3a2-specific Th cells efficiently stimulated the primary expansion of WTI-specific cytotoxic T lymphocytes (CTLs). The expanded CTLs were cytotoxic toward WT1-peptide-loaded HLA-A*24:02-positive cell lines and exerted a potent antileukemic effect in vivo. However, the b3a2-specific Th-clone-mediated antileukemic CTL responses were strongly inhibited by both TKIs and interferon-α. Our findings indicate a crucial role of b3a2-specific Th cells in leukemia antigen-specific CTL-mediated immunity and provide an experimental basis for establishing novel CML immunotherapies.

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“…We previously established a method to induce the proliferation of human induced pluripotent stem (iPS) cell‐derived myeloid cells to generate iPS cell‐derived myeloid/macrophage cell lines (iPS‐ML) . Similar to physiological macrophages, iPS‐ML cells expressed various receptors related to tissue infiltration.…”

Section: Introductionmentioning

confidence: 99%

“…We previously established a method to induce the proliferation of human induced pluripotent stem (iPS) cell-derived myeloid cells to generate iPS cell-derived myeloid/macrophage cell lines (iPS-ML). [27][28][29] Similar to physiological macrophages, iPS-ML cells expressed various receptors related to tissue infiltration. When human iPS-ML cells were injected into severe combined immunodeficiency (SCID) mice bearing cancers (xenograft cancer models), iPS-ML cells accumulated and infiltrated into the cancer tissues, indicating a cancerdirected migration capacity of iPS-ML.…”

Section: Introductionmentioning

confidence: 99%

Cancer therapy with major histocompatibility complex‐deficient and interferon β‐producing myeloid cells derived from allogeneic embryonic stem cells

et al. 2019

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We previously established a method to generate myeloid cells with a proliferative capability from pluripotent stem cells and designated them iPS‐ML. Human iPS‐ML cells share features with physiological macrophages including the capability to infiltrate into cancer tissues. We observed therapeutic effects of human iPS‐ML cells expressing interferon β (iPS‐ML/interferon (IFN)‐β) in xenograft cancer models. However, assessment of host immune system‐mediated therapeutic and adverse effects of this therapy is impossible by xenograft models. We currently evaluated the therapeutic effects of a mouse equivalent of human iPS‐ML/IFN, a mouse embryonic stem (ES) cell‐derived myeloid cell line producing IFN (ES‐ML/IFN). The ES‐MLs producing IFN‐β (β‐ML) and IFN‐γ (γ‐ML) and originating from E14 ES cells derived from the 129 mouse strain (H‐2b) were generated, and the MHC (H‐2Kb, Db, and I‐Ab) genes of the ES‐ML/IFN were disrupted using the clustered regularly interspaced short palindromic repeats (CRISPR)/CAS9 method. We used the ES‐ML/IFN to treat allogeneic BALB/c mice (H‐2d) transplanted with Colon26 cancer cells. Treatment with β‐ML but not with γ‐ML cells repressed the growth of colon cancer in the peritoneal cavity and liver. The transferred ES‐ML/IFN infiltrated into cancer tissues and enhanced infiltration of T cells into cancer tissues. ES‐ML/IFN therapy increased the number of immune cells in the lymphoid organs. Sensitization of both cancer antigen‐specific CD8+ T cells and natural killer (NK) cells were enhanced by the therapy, and CD8+ T cells were essential for the therapeutic effect, implying that donor MHC‐deficient β‐ML exhibited a therapeutic effect through the activation of host immune cells derived from allogeneic recipient mice. The results suggested the usefulness of HLA‐deficient human iPS‐ML/IFN‐β cells for therapy of HLA‐mismatched allogeneic cancer patients.

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Generation of Mouse Pluripotent Stem Cell–Derived Proliferating Myeloid Cells as an Unlimited Source of Functional Antigen-Presenting Cells

Cited by 18 publications

References 47 publications

Immunogenic Dendritic Cell Generation from Pluripotent Stem Cells by Ectopic Expression of Runx3

Immunogenic Dendritic Cell Generation from Pluripotent Stem Cells by Ectopic Expression of Runx3

BCR–ABL-specific CD4+ T-helper cells promote the priming of antigen-specific cytotoxic T cells via dendritic cells

Cancer therapy with major histocompatibility complex‐deficient and interferon β‐producing myeloid cells derived from allogeneic embryonic stem cells

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