α-Type-1 Polarized Dendritic Cells

Mailliard, Robbie B.; Wańkowicz-Kalińska, Anna; Cai, Quan; Wesa, Amy; Hilkens, Catharien M. U.; Kapsenberg, Martien L.; Kirkwood, John M.; Storkus, Walter J.; Kaliński, Paweł

doi:10.1158/0008-5472.can-04-1261

Cited by 435 publications

(222 citation statements)

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“…In immune cells, CCR7 signal transduction is activated by proinflammatory cytokines (Mailliard et al, 2004), and appears to be mediated by PI3Ks, a family of lipid kinases that play a crucial role in cellular processes associated with malignant behavior, including cell growth, migration, and survival (Benistant et al, 2000;Mills et al, 2001;Luo et al, 2003). Once activated, Akt/PKB inhibits cell death pathways by directly phosphorylating and inactivating proapoptotic proteins, including Bad and procaspase 9 (Datta et al, 1999;Amornphimoltham et al, 2004;Wells and Lillien, 2004).…”

Section: Introductionmentioning

confidence: 99%

Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR

et al. 2005

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Chemokine receptor 7 (CCR7) upregulation, which mediates immune cell survival and migration to lymph nodes, has recently been associated with nodal metastasis of squamous cell carcinoma of the head and neck (SCCHN). However, the mechanism of CCR7 in tumor progression, its downstream signaling mediators, and interactions with other pathways contributing to metastasis of SCCHN have not been determined. We hypothesized that inflammatory chemokine-mediated signals could also promote tumor proliferation and mitogenic effects. Functional assays showed that chemotaxis and invasion of metastatic SCCHN cells were dependent on phosphoinositide-3 kinase (PI3K) and its substrate, activated phospholipase Cc-1. In addition, treatment of CCR7 þ metastatic SCCHN cells with CCL19 (MIP-3b) showed rapid activation of the prosurvival, PI3K/Akt pathway. Transactivation of EGFR-mediated and mitogen-activated protein kinase signaling pathways, which can promote migration and survival in parallel, did not appear to contribute to the functional or biochemical effects of CCR7 stimulation. Thus, proinflammatory chemokine signals that mediate activation, trafficking and survival of tumor-infiltrating immune cells in the tumor microenvironment actually appear to induce signals for progression of cancer cells. The CCR7-mediated pathway in metastatic SCCHN cells functions independently of EGFR signal transduction and therefore may represent an additional target for therapeutic intervention to prevent tumor progression and metastasis.

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Section: Introductionmentioning

confidence: 99%

Chemokine receptor 7 activates phosphoinositide-3 kinase-mediated invasive and prosurvival pathways in head and neck cancer cells independent of EGFR

et al. 2005

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“…These observed reductions in CD80 and CD83 expression were not statistical significant but consistent in all donors. It was previously published that IL-12p70 secretion was dependent on IFN-γ or Poly-I:C with the largest contribution from IFN-γ [5]. For T cell activation, αDC1s have been shown to be superior for CTL activation [5], whereas assays mostly reflecting CD4+ T cell responses has demonstrated a decreased capacity for T cell activation as compared to sDCs [4].…”

Section: Phenotype After Maturationmentioning

confidence: 99%

“…th tance and may increase the efficiency of this vaccine strategy. αDC1s have been shown to be superior in IL-12p70 secretion and CTL activation [5]. Viability of therapeutic DCs is another factor of potential importance as DCs may exert their effect in vivo after more than 24 hours upon injection.…”

Section: Poly-i:c Mediated Effects On Pkr Expression and Activationmentioning

confidence: 99%

“…DCs maturated according to the standard cytokine cocktail consisting of TNF-α/IL-1β/IL-6 and PGE 2 [3] show high expression of maturation markers CD80, CD83, CD86, CD134L and CCR7, but low secretion of IL-12p70 [4] which may have negative consequences for activation of appropriate T cell responses such as TH1 cells and cytotoxic T lymphocytes (CTLs). In the search of cytokine cocktails that increase DC IL-12p70 secretion, DCs maturated according to the α-Type-1 polarizing cocktail containing TNF-α/IL-1β/ Poly-I:C/IFN-α and IFN-γ were developed, as these DCs produce large amounts of IL-12p70 [4,5]. We and others have characterized cytokine secretion and capacity for T cell activation in details elsewhere [4,5] and it has been found that αDC1s may have a reduced capacity for T cell activation under certain conditions [4].…”

Section: Introductionmentioning

confidence: 99%

“…In the search of cytokine cocktails that increase DC IL-12p70 secretion, DCs maturated according to the α-Type-1 polarizing cocktail containing TNF-α/IL-1β/ Poly-I:C/IFN-α and IFN-γ were developed, as these DCs produce large amounts of IL-12p70 [4,5]. We and others have characterized cytokine secretion and capacity for T cell activation in details elsewhere [4,5] and it has been found that αDC1s may have a reduced capacity for T cell activation under certain conditions [4]. In addition to the criterias for successful DC generation investigated elsewhere, viability is an important factor.…”

Section: Introductionmentioning

confidence: 99%

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Poly-I:C Decreases Dendritic Cell Viability Independent of PKR Activation

Larsen¹,

Pedersen²

2012

JIBTVA

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Vaccination with tumor-antigen pulsed, monocyte-derived dendritic cells (DCs) has emerged as a promising strategy in cancer immunotherapy. The standard DC maturation cocktail consists of a combination of tumor necrosis factor-α (TNF-α)/interleukin (IL)-1β/IL-6 and prostaglandin E 2 (PGE 2 ) for generation of standard DCs (sDCs). In order to improve IL-12p70 production and cytotoxic T-lymphocyte (CTL) induction, a novel cocktail composed of TNF-α/IL-1β/ interferon (IFN)-α/IFN-γ and polyinosinic:polycytidylic acid (Poly-I:C) has been introduced to generate so-called α-Type-1 polarized DCs (αDC1s). We and others have previously performed a comprehensive comparison of sDCs and αDC1s. Here we demonstrate that the viability of αDC1s is lowered compared to sDCs and that DC apoptosis is mediated by Poly-I:C. We speculated that activation of protein kinase R (PKR) could mediate the observed apoptosis, but despite significantly higher PKR expression in αDC1s compared to sDCs and induction of active threonine (Thr)446 autophosphorylation of PKR in αDC1s, Poly-I:C did not influence total PKR expression or autophosporylation, indicating PKR-independent Poly-I:C-induced DC apoptosis.

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