Activated human umbilical cord blood dendritic cells kill tumor cells without damaging normal hematological progenitor cells

Shi, Jun; Ikeda, Kazuma; Fujii, Nobuharu; Kondo, Eisei; Shinagawa, Katsuji; Ishimaru, Fumihiko; Kaneda, Kinuyo; Tanimoto, Mitsune; Li, Xiao; Qin, Pu

doi:10.1111/j.1349-7006.2005.00017.x

Cited by 30 publications

(32 citation statements)

References 30 publications

(29 reference statements)

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“…In the present study we have described the direct susceptibility of tumor cells to DCs through Irp94-NKR-P2 interaction. Fas-FasL interaction, TRAIL up-regulation, and the tumoricidal action of DCs have been demonstrated earlier with native and various subsets of DCs (10,39,40). In the present study we have demonstrated a novel surface interaction between rat DCs and tumor cells (NKR-P2-Irp94) that mediates specific and specialized killing of tumors.…”

Section: Discussionmentioning

confidence: 59%

The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation

Srivastava

Varalakshmi

Khar

2008

The Journal of Immunology

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Tumor recognition and killing, the uptake of released immunogenic substrate, and the generation of immunity are crucial aspects of dendritic cell (DC)-mediated antitumor immune response. In the context of direct tumoricidal activity, we have recently shown NK cell receptor protein-2 (NKR-P2)/NK group 2 member D (NKG2D) as a potent activation receptor on rat DCs. The activation of DCs with agonistic anti-NKR-P2 mAb, the binding of soluble NKR-P2 to the AK-5 tumor, and DC maturation with fixed AK-5 cells led us to identify a putative NKR-P2 ligand on the AK-5 cell surface. In this study we have shown that the AK-5 tumor-derived ischemia-responsive protein-94 (Irp94, a 110 kDa Hsp family member) acts as a functional ligand for NKR-P2 on DCs and enhances Irp94-NKR-P2 interaction-dependent tumor cell apoptosis via NO. Surface expression of Irp94 was also found on tumors of diverse origin in addition to AK-5. Furthermore, the Th1-polarizing cytokine IL-12, produced from Irp94-ligated BMDCs, augments NK cell cytotoxicity. Irp94-NKR-P2 interaction drives the maturation of BMDCs by up-regulating MHC class II, CD86, and CD1a and also induces autologous T cell proliferation, which displays a crucial state of DCs for adaptive antitumor immune response. These functional properties of Irp94 reside in the COOH terminus subdomain but not in the NH2 terminus ATPase domain of Irp94. We also show the involvement of PI3K, ERK, protein kinase C, phosphatases, and NF-κB translocation as downstream mediators of DCs activation upon NKR-P2 ligation with Irp94. Our studies demonstrate for the first time a novel role of a 110-kDa heat shock protein (Irp94) as a ligand for NKR-P2 on DCs, which in turn executes both innate and adaptive immunity.

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Section: Discussionmentioning

confidence: 59%

The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation

Srivastava

Varalakshmi

Khar

2008

The Journal of Immunology

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“…However, when stimulated with LPS, these DC kill the Daudi and Jurkat, but not the HL-60, target cells. 40 Both treatments appear to upregulate DC expression of intracellular TRAIL with little effect on TNF or FasL, although the functional role of these TNF family members in tumor cell killing by DC was not investigated. CD34…”

Section: Cultured Kdc Generated From Bone Marrow Progenitor Cells or mentioning

confidence: 99%

Killer dendritic cells: mechanisms of action and therapeutic implications for cancer

Wesa

Storkus

2007

Cell Death Differ

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Dendritic cells (DC) are essential for the development and regulation of adaptive host immune responses against tumors. DC are heterogeneous and comprised of diverse cellular subsets. They are best known for mediating a crucial role in the initiation of acquired immunity by serving as professional antigen presenting cells (APC) that take up antigens in their local microenvironment, which are then processed and presented to naïve T cells in the context of major histocompatibility complex (MHC) class I and II molecules. In addition to these functions, DC can modulate the types of T cell responses they generate, and can also influence the responses of innate effectors, such as NK cells. There is also now evidence that they may mediate a more primordial role as innate, effector cells that are tumoricidal. 'Killer' DC (KDC) may represent a true 'multi-tasking' cell type that can sequentially act as a 'hunter-gatherer' of antigens; as well as, an instructor, then enforcer/regulator, of antigenspecific anti-tumor T-cell responses in vivo. In this review, we will critically examine the published record regarding KDC, their mechanism(s) of action, and then consider the potential integration of KDC into novel immunotherapies for patients with cancer.

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“…In addition, the role of these killer cells in the induction and maintenance of the antitumoral immune response has not been fully elucidated. We report in this study that the TLR-4 ligand LPS (6,14,15,19,20) was capable of inducing the tumoricidal activity of CD11c + -selected murine BMDCs. The synthetic bacterial lipopeptide Pam3Cys-SK4 (Pam, a TLR-2 agonist) was highlighted as an additional inducer of DC killing potential.…”

mentioning

confidence: 99%

“…In humans, peripheral blood (8,10,13,14,18), umbilical cord blood CD34 + (19), or monocyte-derived (6,12,19,24,26) DCs exhibiting spontaneous or induced tumoricidal abilities have also been characterized. The killing mechanisms employed by these cytolytic cells are various and may involve the death receptor ligand TRAIL (5,8,12,13,17,19,21,25), the perforin/granzyme (21), the Fas/FasL (26), or the CD40/CD40L systems (9).…”

mentioning

confidence: 99%

“…Several subsets of cytotoxic DCs have been described in mice, rats, and humans . The killing potential of these cells may be spontaneous (10,14) or induced by a variety of signals, such as TLR ligands including LPS (6,14,15,19,20), imiquimod (5,21), or CpG (5, 7), by cytokines, such as IFN-g (6,8,12,14,18,19,25), or by CD40L (25). In mice, tumor cell apoptosis induced by bone marrow-derived DCs (BMDCs) may depend on NO but also on undefined proapoptotic factor(s) (20).…”

mentioning

confidence: 99%

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Peroxynitrite-Dependent Killing of Cancer Cells and Presentation of Released Tumor Antigens by Activated Dendritic Cells

Fraszczak

Trad

Janikashvili

et al. 2010

The Journal of Immunology

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Activated human umbilical cord blood dendritic cells kill tumor cells without damaging normal hematological progenitor cells

Cited by 30 publications

References 30 publications

The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation

The Ischemia-Responsive Protein 94 (Irp94) Activates Dendritic Cells through NK Cell Receptor Protein-2/NK Group 2 Member D (NKR-P2/NKG2D) Leading to Their Maturation

Killer dendritic cells: mechanisms of action and therapeutic implications for cancer

Peroxynitrite-Dependent Killing of Cancer Cells and Presentation of Released Tumor Antigens by Activated Dendritic Cells

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