Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN

Kim, Jin Hee; Kang, Tae Heung; Noh, Kyung Hee; Kim, Seok Ho; Lee, Young Ho; Kim, Keon Woo; Bae, Hyun Cheol; Ahn, Yeong Hee; Choi, Eun Young; Kim, Jin Seok; Lee, Kyung Mi; Kim, Tae Woo

doi:10.1016/j.imlet.2010.08.008

Cited by 36 publications

(27 citation statements)

References 26 publications

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“…Increased signaling improves survival of DCs and their precursors, and these cells can even be rescued from GM-CSF deprivation-induced apoptosis by ectopic activation of this pathway. 42,49,50 Although the survival of most DC lineages appears to be supported by PI3K-dependent signaling, important differences between distinct subsets and differentiation phases have been observed. For instance, human CD34-derived pre-interstitial DCs and pre-Langerhans cells require PI3K activity to survive, but the survival of terminally differentiated DCs of these lineages is independent of PI3K or mTOR activity.…”

Section: Pi3k/pkbmentioning

confidence: 99%

“…Indeed, mouse bone marrow-derived conventional DCs and human monocyte-derived DCs expressing constitutively active PKB or lacking PTEN activity because of siRNA-mediated deletion are highly activated DCs with improved longevity that are able to eradicate tumors more efficiently than control DCs. 49,50 Based on its decisive function in DC lineage commitment, 28,29,32 STAT5 appears a candidate protein for the manipulation of subset specification. Alternatively, the STAT5-regulated factors that are responsible for its effects on lineage decisions, such as PU.1 or IRF8, or the subset-specific regulator RelB 66,79 could be targeted.…”

Section: Clinical Applicationmentioning

confidence: 99%

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Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy

Laar

Coffer

Woltman

2012

Blood

288

217

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Dendritic cells (DCs) represent a small and heterogeneous fraction of the hematopoietic system, specialized in antigen capture, processing, and presentation. The different DC subsets act as sentinels throughout the body and perform a key role in the induction of immunogenic as well as tolerogenic immune responses. Because of their limited lifespan, continuous replenishment of DC is required. Whereas the importance of GM-CSF in regulating DC homeostasis has long been underestimated, this cytokine is currently considered a critical factor for DC development under both steady-state and inflammatory conditions. Regulation of cellular actions by GM-CSF depends on the activation of intracellular signaling modules, including JAK/STAT, MAPK, PI3K, and canonical NF-κB. By directing the activity of transcription factors and other cellular effector proteins, these pathways influence differentiation, survival and/or proliferation of uncommitted hematopoietic progenitors, and DC subset–specific precursors, thereby contributing to specific aspects of DC subset development. The specific intracellular events resulting from GM-CSF–induced signaling provide a molecular explanation for GM-CSF–dependent subset distribution as well as clues to the specific characteristics and functions of GM-CSF–differentiated DCs compared with DCs generated by fms-related tyrosine kinase 3 ligand. This knowledge can be used to identify therapeutic targets to improve GM-CSF–dependent DC-based strategies to regulate immunity.

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Section: Pi3k/pkbmentioning

confidence: 99%

Section: Clinical Applicationmentioning

confidence: 99%

Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy

Laar

Coffer

Woltman

2012

Blood

288

217

View full text Add to dashboard Cite

show abstract

“…Although these and other issues need to be resolved before our findings can be translated into novel therapies, similar strategies have been applied to promote the functionality of murine and human myeloid DCs without significant side effects. 18,46 This indicates that with careful consideration of the disease and potential side effects, the PI3K-PKB-mTOR axis may provide a useful therapeutic target. …”

Section: Org Frommentioning

confidence: 99%

PI3K-PKB hyperactivation augments human plasmacytoid dendritic cell development and function

Laar¹,

Bosch²,

Boonstra³

et al. 2012

Blood

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Plasmacytoid dendritic cells (pDCs) are considered potential tools or targets for immunotherapy. However, current knowledge concerning methodologies to manipulate their development or function remains limited. Here, we investigated the role of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-mammalian target of rapamycin (mTOR) axis in human pDC development, survival, and function. In vitro pDC generation from human cord blood-derived CD34 ؉ hematopoietic progenitors was reduced by pharmacologic inhibition of PI3K, PKB, or mTOR activity, and peripheral blood pDCs required PI3K-PKB-mTOR signaling to survive. Accordingly, activity of this pathway in circulating pDCs correlated with their abundance in peripheral blood. Importantly, introduction of constitutively active PKB or pharmacologic inhibition of negative regulator phosphatase and tensin homolog (PTEN) resulted in increased pDC numbers in vitro and in vivo. Furthermore, MHC class II and costimulatory molecule expression, and production of IFN-␣ and TNF-␣, were augmented, which could be explained by enhanced IRF7 and NF-B activation. Finally, the numerically and functionally impaired pDCs of chronic hepatitis B patients demonstrated reduced PI3K-PKB-mTOR activity. In conclusion, intact PI3K-PKB-mTOR signaling regulates development, survival, and function of human pDCs, and pDC development and functionality can be promoted by PI3K-PKB hyperactivation. Manipulation of this pathway or its downstream targets could be used to improve the generation and function of pDCs to augment immunity. (Blood. 2012; 120(25):4982-4991) IntroductionPlasmacytoid dendritic cells (pDCs) represent a specialized DC subset that is recognized for its unique ability to rapidly produce large amounts of type 1 interferons (IFN-␣␤) on the interaction with viruses or nucleic acids of self or nonself origin. 1 Besides direct antiviral activity through the production of IFN-␣␤, pDCs have been implicated in playing a broader role in immunity. pDC activation results in the production of additional proinflammatory cytokines such as TNF-␣ and IL-6, and it stimulates the expression of MHC class I, MHC class II, and costimulatory molecules. These combined functions enable pDCs to activate T helper cells, cytotoxic T lymphocytes, natural killer cells, and plasma cell differentiation. Moreover, pDC-derived cytokines can act as adjuvants for other DC subsets such as myeloid or conventional DC. In contrast, tolerogenic functions of pDC, including the generation of regulatory T cells, have also been described. Similar to other DC subsets, pDC thus show the dual capability of being able to initiate as well as regulate immunity. [1][2][3] In accordance with their broad role in the regulation of immunity, the possibilities to use pDC as either tools or targets for immunotherapy are being increasingly explored. Activation of dysfunctional tumor-resident pDCs may be achieved by administration of TLR agonists, 4,5 and methods to induce antitumor responses by either targeting antigen to endogeno...

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“…Attending that activation of PI3K/Akt and MAPK exerts a central role in DCs function [22,23] as during interaction of RNA virus with host cells [24,25]. We decided to study signaling differences between inactivated or infective FMDV virus.…”

Section: Fmdv Activates Erk1/2 Mapk Pathwaymentioning

confidence: 99%

Foot-and-mouth disease virus infection of dendritic cells triggers phosphorylation of ERK1/2 inducing class I presentation and apoptosis

Langellotti

Cesar

Soria

et al. 2015

Vaccine

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Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN

Cited by 36 publications

References 26 publications

Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy

Regulation of dendritic cell development by GM-CSF: molecular control and implications for immune homeostasis and therapy

PI3K-PKB hyperactivation augments human plasmacytoid dendritic cell development and function

Foot-and-mouth disease virus infection of dendritic cells triggers phosphorylation of ERK1/2 inducing class I presentation and apoptosis

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