An essential role for Akt1 in dendritic cell function and tumor immunotherapy

Park, Dongsu; Lapteva, Natalia; Seethammagari, Mamatha; Slawin, Kevin M.; Spencer, David M.

doi:10.1038/nbt1262

Cited by 99 publications

(122 citation statements)

References 50 publications

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“…We previously revealed defective Akt activation and Bcl-2 expression along with increased apoptosis in DC from db/db mice (11). A recent study shows that Akt is required for LPS-mediated DC maturation (33). Here, we demonstrate that Akt is critical for CD40 induction by leptin and links both leptin receptor and TLR4 activation to the downstream transcription factors STAT-1␣ and NF-Bp65.…”

Section: Discussionmentioning

confidence: 64%

Leptin Induces CD40 Expression through the Activation of Akt in Murine Dendritic Cells

Lam

Zheng

Jin

et al. 2007

Journal of Biological Chemistry

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Increasing evidence suggests a regulatory role for leptin, an adipocyte-derived hormone, in immunity. Although recent studies indicated an essential role of leptin signaling in dendritic cell (DC) maturation, the molecular mechanisms by which leptin modulates DC functional maturation remained unclear. In this study, we showed that leptin induced CD40 expression in murine DC and significantly up-regulated their immunostimulatory function in driving T cell proliferation. Moreover, leptin markedly enhanced lipopolysaccharide-mediated DC activation. Using pharmacological inhibitors for Akt, STAT-1␣, or NF-B and the dominant negative forms of Akt and IB kinase ␣/␤/␥, as well as small interfering RNA for STAT-1␣, we showed that Akt, STAT-1␣, and NF-B were important for the leptin-or lipopolysaccharide-induced CD40 expression. Coimmunoprecipitation analysis revealed that leptin promoted immune complex formation between Akt and the IB kinase subunits as well as STAT-1␣. Blocking the activity of Akt demonstrated a crucial role for Akt in translocation of STAT-1␣ and NF-B to the nucleus and activation of the CD40 promoter. Further analysis with chromatin immunoprecipitation assay confirmed that leptin recruited STAT-1␣, NF-Bp65, and RNA polymerase II to the CD40 promoter and enhanced histone 4 acetylation in a time-dependent manner. Thus, our results have elucidated the molecular mechanisms underlying leptin-induced CD40 expression and DC maturation.Leptin, encoded by the obese (ob) gene, is an adipocyte-derived hormone that has long been recognized as a satiety factor in regulating nutrient intake and energy homeostasis (1). Leptin is structurally related to members of the long chain helical cytokines such as IL-6, 2 IL-11, IL-12, and granulocyte colony-stimulating factor. The leptin receptor (Ob-R), a member of class I cytokine receptors, is encoded by the diabetes (db) gene and is expressed in peripheral B cells, T cells, NK cells, and monocyte macrophages (2-6). Leptin has been increasingly recognized as a cytokine-like hormone with pleiotropic actions in modulating immune responses (7). It has been shown that leptin can modulate the adaptive immunity via enhancing T cell survival and stimulating their production of pro-inflammatory cytokines such as interferon ␥ and IL-2 (8). Moreover, leptin activates NK cells and monocyte macrophages and enhances their immune functions and cytokine production (3, 9). Recent studies indicate that leptin promotes differentiation and survival of human DC (10). We also demonstrated the expression of functional leptin receptor on murine DC and revealed significantly impaired maturation and survival of bone marrow (BM)-derived DC in leptin-receptor deficient db/db mice (11), but the underlying molecular mechanisms by which leptin regulates DC maturation and function remained largely unclear. DC are the most potent antigen-presenting cells and undergo maturation process by up-regulating the expression of MHC and costimulatory molecules and become phenotypically and functionally differenti...

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Section: Discussionmentioning

confidence: 64%

Leptin Induces CD40 Expression through the Activation of Akt in Murine Dendritic Cells

Lam

Zheng

Jin

et al. 2007

Journal of Biological Chemistry

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“…Many studies have demonstrated that anti-tumor immunity and the ability to break tolerance could be enhanced by co-delivering additional immunomodulator genes, such as interleukin-2, interleukin-12, interleukin-15, CD70 and other activators, to DCs. 5,[57][58][59][60] We are currently conducting experiments to evaluate the anti-tumor immunity generated by the co-delivery of a tumor antigen and an immuomodulator using this DC-directed lentivector system.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell-directed lentivector vaccine induces antigen-specific immune responses against murine melanoma

Yang

Liang

et al. 2011

Cancer Gene Ther

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Lentivectors are potential vaccine delivery vehicles because they can efficiently transduce a variety of non-dividing cells, including antigen-presenting cells, and do not cause expression of extra viral proteins. To improve safety while retaining efficiency, a dendritic cell (DC)-specific lentivector was constructed by pseudotyping the vector with an engineered viral glycoprotein derived from Sindbis virus. We assessed the level of anti-tumor immunity conferred by this engineered lentivector encoding the melanoma antigen gp100 in a mouse model. Footpad injection of the engineered lentivectors results in the best antigen-specific immune response as compared with subcutaneous and intraperitoneal injections. A single prime vaccination of the engineered lentivectors can elicit a high frequency (up to 10%) of gp100-specific CD8 þ T cells in peripheral blood 3 weeks after the vaccination and this response will be maintained at around 5% for up to 8 weeks. We found that these engineered lentivectors elicited relatively low levels of anti-vector neutralizing antibody responses. Importantly, direct injection of this engineered lentivector inhibited the growth of aggressive B16 murine melanoma. These data suggest that DC-specific lentivectors can be a novel and alternative vaccine carrier with the potential to deliver effective anti-tumor immunity for cancer immunotherapy.

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“…25,27-29 Lipofection-or gene gun-mediated gene transduction, however, is highly limited because DCs are generally resistant to nonviral gene delivery methods. In contrast, we previously reported that AdRGD-mediated gene transfer into DCs has up to 98% efficiency.…”

Section: Discussionmentioning

confidence: 99%

Engineering of highly immunogenic long-lived DC vaccines by antiapoptotic protein gene transfer to enhance cancer vaccine potency

et al. 2008

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Dendritic cells (DCs) have a critical role in the induction of antigen-specific immune responses, transporting antigens from peripheral tissue to regional lymph nodes where they interact with antigen-specific T lymphocytes. Recent studies revealed that the efficacy of the T cell-dependent immune response depends on the lifespan of the antigen-presenting DCs in the lymph nodes. Here, we succeeded in engineering long-lived antigen-presenting DCs via Bcl-x L -derived hyperactive mutant antiapoptotic protein (Bcl-x FNK ) gene transfer. In a B16BL6 melanoma model, these long-lived DCs exerted potent antitumor immunity that depended mainly on antigenspecific cytotoxic T lymphocytes. Furthermore, in vivo longevity of the long-lived DC vaccine led to antigen-specific activation of interferon-g-producing CD4 + and CD8 + T cells. Thus, the long-lived DC vaccine strategy is highly useful for constructing DC vaccines, as well as other cell-based medicines, such as stem cell therapy.

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An essential role for Akt1 in dendritic cell function and tumor immunotherapy

Cited by 99 publications

References 50 publications

Leptin Induces CD40 Expression through the Activation of Akt in Murine Dendritic Cells

Leptin Induces CD40 Expression through the Activation of Akt in Murine Dendritic Cells

Dendritic cell-directed lentivector vaccine induces antigen-specific immune responses against murine melanoma

Engineering of highly immunogenic long-lived DC vaccines by antiapoptotic protein gene transfer to enhance cancer vaccine potency

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