Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells

Tsuchiya, Nobuhiro; Zhang, Rong; Iwama, Tatsuaki; Ueda, Naonori; Liu, Tianyi; Tatsumi, Minako; Sasaki, Yutaka; Shimoda, Ranmaru; Osako, Yuki; Sawada, Yu; Kubo, Yosuke; Miyashita, Azusa; Fukushima, Satoshi; Cheng, Zhao; Nakaki, Ryo; Takubo, Keiyo; Okada, Seiji; Kaneko, Shin; Ihn, Hironobu; Kaisho, Tsuneyasu; Nishimura, Yasuharu; Senju, Satoru; Endo, Itaru; Nakatsura, Tetsuya; Uemura, Yukari

doi:10.1016/j.celrep.2019.08.086

Cited by 31 publications

(31 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An important issue related to the clinical use of IFNs is toxicity and adverse events. Although approved in 1986 by the FDA for the treatment of malignancies and viral disorders, with demonstrated positive disease outcomes, IFNa is currently not commonly used in cancer treatment due to adverse effects (36,37). A pilot study looked at the potential of decreasing the dose of IFN-a2b for the treatment of melanoma over the course of an 11-month treatment period.…”

Section: Canonical and Non-canonical Ifn Signaling In Malignanciesmentioning

confidence: 99%

“…Tsuchiya et al genetically engineered induced pluripotent stem cell (iPSC)-derived proliferation myeloid cells (iPSC-pMCs) to produce IFNa. When injected into mice, these IFN-producing iPSC-pMCs exerted immunomodulatory effects analogous to direct type I IFN administration, yet without adverse effects or hematopoietic stem cell exhaustion (37). Brown et al studied recombinant poliovirus/rhinovirus chimera PVSRIPO effects in cancer immunosuppression and found PVSRIPO infection of DCs increased IFNb production and a sustained type I IFN response, as indicated by p-STAT1 and ISG induction (IFIT1, ISG15) (34).…”

Section: Canonical and Non-canonical Ifn Signaling In Malignanciesmentioning

confidence: 99%

See 1 more Smart Citation

Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways

et al. 2020

View full text Add to dashboard Cite

For several decades there has been accumulating evidence implicating type I interferons (IFNs) as key elements of the immune response. Therapeutic approaches incorporating different recombinant type I IFN proteins have been successfully employed to treat a diverse group of diseases with significant and positive outcomes. The biological activities of type I IFNs are consequences of signaling events occurring in the cytoplasm and nucleus of cells. Biochemical events involving JAK/STAT proteins that control transcriptional activation of IFN-stimulated genes (ISGs) were the first to be identified and are referred to as “canonical” signaling. Subsequent identification of JAK/STAT-independent signaling pathways, critical for ISG transcription and/or mRNA translation, are denoted as “non-canonical” or “non-classical” pathways. In this review, we summarize these signaling cascades and discuss recent developments in the field, specifically as they relate to the biological and clinical implications of engagement of both canonical and non-canonical pathways.

show abstract

Section: Canonical and Non-canonical Ifn Signaling In Malignanciesmentioning

confidence: 99%

Section: Canonical and Non-canonical Ifn Signaling In Malignanciesmentioning

confidence: 99%

Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Besides direct targeting approaches, endogenous cDC1 populations could be indirectly modulated by other cell-based immunotherapies. In accordance with this, the administration of IFNα-producing iPSC-derived proliferating myeloid cells (pMCs) to mice strongly activated host CD141 + XCR1 + DCs, enhancing their CD8 + T cell priming capacity and thus boosting anti-tumor immune responses [120]. Furthermore, IFN-α-iPSC-pMCs administered in combination with immune checkpoint inhibitors overcame resistance to single-dose administrations, leading to longer lasting anti-tumor immunity, shedding light on the advantages that may arise from treatment combination [120].…”

Section: Exploiting Cdc1 In Cancer Immunotherapymentioning

confidence: 74%

“…In accordance with this, the administration of IFNα-producing iPSC-derived proliferating myeloid cells (pMCs) to mice strongly activated host CD141 + XCR1 + DCs, enhancing their CD8 + T cell priming capacity and thus boosting anti-tumor immune responses [120]. Furthermore, IFN-α-iPSC-pMCs administered in combination with immune checkpoint inhibitors overcame resistance to single-dose administrations, leading to longer lasting anti-tumor immunity, shedding light on the advantages that may arise from treatment combination [120]. On the other hand, allogenic T cells were recently reported to be able to act as migratory transporters, delivering antigens to resident XCR1 + DCs in secondary lymphoid organs [121].…”

Section: Exploiting Cdc1 In Cancer Immunotherapymentioning

confidence: 74%

Dendritic Cell Vaccines for Cancer Immunotherapy: The Role of Human Conventional Type 1 Dendritic Cells

et al. 2020

View full text Add to dashboard Cite

Throughout the last decades, dendritic cell (DC)-based anti-tumor vaccines have proven to be a safe therapeutic approach, although with inconsistent clinical results. The functional limitations of ex vivo monocyte-derived dendritic cells (MoDCs) commonly used in these therapies are one of the pointed explanations for their lack of robustness. Therefore, a great effort has been made to identify DC subsets with superior features for the establishment of effective anti-tumor responses and to apply them in therapeutic approaches. Among characterized human DC subpopulations, conventional type 1 DCs (cDC1) have emerged as a highly desirable tool for empowering anti-tumor immunity. This DC subset excels in its capacity to prime antigen-specific cytotoxic T cells and to activate natural killer (NK) and natural killer T (NKT) cells, which are critical factors for an effective anti-tumor immune response. Here, we sought to revise the immunobiology of cDC1 from their ontogeny to their development, regulation and heterogeneity. We also address the role of this functionally thrilling DC subset in anti-tumor immune responses and the most recent efforts to apply it in cancer immunotherapy.

show abstract

“…36 Nevertheless, although the frequency of the mutant Adpgk allele in the MC38 cancer used in this study was approximately 30%, the transplanted MC38 cancer was completely suppressed in combination therapies in some mice. 45 This may be due to the successful elimination of cancer, triggered by an "epitope spreading". 46 Only a single T cell epitope targeting a single cancer antigen was used in this study.…”

Section: Discussionmentioning

confidence: 99%

Generation of GM-CSF-producing antigen-presenting cells that induce a cytotoxic T cell-mediated antitumor response

et al. 2020

Self Cite

View full text Add to dashboard Cite

Immunotherapy using dendritic cells (DCs) is a promising treatment modality for cancer. However, the limited number of functional DCs from peripheral blood has been linked to the unsatisfactory clinical efficacies of current DC-based cancer immunotherapies. We previously generated proliferating antigen-presenting cells (APCs) by genetically engineering myeloid cells derived from induced pluripotent stem cells (iPSC-pMCs), which offer infinite functional APCs for broad applications in cancer therapy. Herein, we aimed to further enhance the antitumor effect of these cells by genetic modification. GM-CSF gene transfer did not affect the morphology, or surface phenotype of the original iPSC-pMCs, however, it did impart good viability to iPSC-pMCs. The resultant cells induced GM-CSF-dependent CD8 + T cell homeostatic proliferation, thereby enhancing antigen-specific T cell priming in vitro. Administration of the tumor antigen-loaded GM-CSF-producing iPSC-pMCs (GM-pMCs) efficiently stimulated antigen-specific T cells and promoted effector cell infiltration of the tumor tissues, leading to an augmented antitumor effect. To address the potential tumorigenicity of iPSCderived products, irradiation was applied and found to restrict the proliferation of GM-pMCs, while retaining their T cell-stimulatory capacity. Furthermore, the irradiated cells exerted an antitumor effect equivalent to that of bone marrow-derived DCs obtained from immunocompetent mice. Additionally, combination with immune checkpoint inhibitors increased the infiltration of CD8 + or NK1.1 + effector cells and decreased CD11b + /Gr-1 + cells without causing adverse effects. Hence, although GM-pMCs have certain characteristics that differ from endogenous DCs, our findings suggest the applicability of these cells for broad clinical use and will provide an unlimited source of APCs with uniform quality.

show abstract

Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells

Cited by 31 publications

References 42 publications

Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways

Type I Interferon (IFN)-Regulated Activation of Canonical and Non-Canonical Signaling Pathways

Dendritic Cell Vaccines for Cancer Immunotherapy: The Role of Human Conventional Type 1 Dendritic Cells

Generation of GM-CSF-producing antigen-presenting cells that induce a cytotoxic T cell-mediated antitumor response

Contact Info

Product

Resources

About