Glycogen Synthase Kinase-3β (GSK-3β) Inhibition Enhances Dendritic Cell-based Cancer Vaccine Potency via Suppression of Interferon-γ-induced Indoleamine 2,3-Dioxygenase Expression

Noh, Kyung Tae; Son, Kwang Hee; Jung, In Duk; Kang, Tae Heung; Choi, Chang Hun; Park, Yeong‐Min

doi:10.1074/jbc.m114.628578

Cited by 18 publications

(13 citation statements)

References 26 publications

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“…To determine the potential therapeutic efficacy of CH (OVA+poly I:C)-NPs, we selected EG.7-OVA cells, which are attractive tumor cells for studying an OVA-based mouse model in terms of immunotherapy2728. Seven days after the s.c. injection of EG.7-OVA tumor cells into C57BL/6 mice, the mice were randomly allocated to the following groups (n = 6 mice per group): (1) control, (2) soluble OVA (100 μg), (3) CH-NPs without OVA and poly I:C, and (4) CH (OVA+poly I:C)-NPs (100 μg of OVA and 80 μg of poly I:C).…”

Section: Resultsmentioning

confidence: 99%

In vivo stepwise immunomodulation using chitosan nanoparticles as a platform nanotechnology for cancer immunotherapy

Han

Byeon

Jang

et al. 2016

Sci Rep

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Dentritic cell (DC)-based cancer immunotherapy faces challenges in both efficacy and practicality. However, DC-based vaccination requires multiple injections and elaborates ex vivo manipulation, which substantially limits their use. Therefore, we sought to develop a chitosan nanoparticle (CH-NP)-based platform for the next generation of vaccines to bypass the ex vivo manipulation and induce immune responses via active delivery of polyinosinic-polycytidylic acid sodium salt (poly I:C) to target Toll-like receptor 3 (TLR3) in endosomes. We developed CH-NPs encapsulating ovalbumin (OVA) as a model antigen and poly I:C as the adjuvant in an ionic complex. These CH-NPs showed increased in vivo intracellular delivery to the DCs in comparison with controls after injection into tumor-bearing mice, and promoted DC maturation, leading to emergence of antigen-specific cytotoxic CD8+ T cells. Finally, the CH-NPs showed significantly greater antitumor efficacy in EG.7 and TC-1 tumor-bearing mice compared to the control (p < 0.01). Taken together, these data show that the CH-NP platform can be used as an immune response modulatory vaccine for active cancer immunotherapy without ex vivo manipulation, thus resulting in increased anticancer efficacy.

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Section: Resultsmentioning

confidence: 99%

In vivo stepwise immunomodulation using chitosan nanoparticles as a platform nanotechnology for cancer immunotherapy

Han

Byeon

Jang

et al. 2016

Sci Rep

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“…Generation and Culture of Dendritic Cells-Primary culture of bone marrow-derived dendritic cells (BMDCs) was performed as described previously (24). Briefly, BM was flushed from the tibiae and femora of 6-to 8-week-old male C57BL/6 mice and depleted of red blood cells using red blood cell lysing buffer (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

Platelet-activating Factor Mediates Endotoxin Tolerance by Regulating Indoleamine 2,3-Dioxygenase-dependent Expression of the Suppressor of Cytokine Signaling 3

Noh

Jung

Sun

et al. 2017

Journal of Biological Chemistry

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Indoleamine 2,3-dioxygenase (IDO) mediates immune tolerance, and suppressor of cytokine signaling 3 (SOCS3) negatively regulates the JAK/STAT signal transduction pathway. We determined previously that platelet-activating factor (PAF) protects mice against LPS-induced endotoxic shock, but its detailed mechanism of action was unknown. We performed survival experiments in and mice using an LPS-induced endotoxemia model and rated organ injury (neutrophil infiltration and liver function). Using ELISA and Western blotting, we also investigated the mechanism of PAF-mediated endotoxin tolerance during endotoxemia. PAF-mediated endotoxin tolerance was dependent on IDO and and was not observed in mice. JAK/STAT signaling, crucial for SOCS3 expression, was also impaired in the absence of IDO. In an IDO- and STAT-dependent manner, PAF mediated a decrease in IL-12 and a dramatic increase in IL-10 and reduced mouse mortality. In addition, PAF attenuated LPS-mediated neutrophil infiltration into the lungs and interactions between neutrophil-like (THP-1) and endothelial cells (human umbilical vein endothelial cells). These results indicate that PAF-mediated endotoxin tolerance is initiated via IDO- and JAK/STAT-dependent expression of SOCS3. Our study has revealed a novel tolerogenic mechanism of IDO action and an important association between IDO and SOCS3 with respect to endotoxin tolerance.

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“…Several inhibitors of GSK3β are in various stages of development, e.g., tideglusib (Table 1) (184). Additionally, in a DC-based tumor vaccination murine model, inhibition of GSK3β by siRNA enhanced CTL activity via suppression of IDO expression (185). …”

Section: Targeting Cell Regulatory Pathways and Immune Checkpoints Asmentioning

confidence: 99%

Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination

Jayashankar

Hafner

2016

Front. Immunol.

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Tuberculosis (TB) remains a global health threat of alarming proportions, resulting in 1.5 million deaths worldwide. The only available licensed vaccine, Bacillus Calmette–Guérin, does not confer lifelong protection against active TB. To date, development of an effective vaccine against TB has proven to be elusive, and devising newer approaches for improved vaccination outcomes is an essential goal. Insights gained over the last several years have revealed multiple mechanisms of immune manipulation by Mycobacterium tuberculosis (Mtb) in infected macrophages and dendritic cells that support disease progression and block development of protective immunity. This review provides an assessment of the known immunoregulatory mechanisms altered by Mtb, and how new interventions may reverse these effects. Examples include blocking of inhibitory immune cell coreceptor checkpoints (e.g., programed death-1). Conversely, immune mechanisms that strengthen immune cell effector functions may be enhanced by interventions, including stimulatory immune cell coreceptors (e.g., OX40). Modification of the activity of key cell “immunometabolism” signaling pathway molecules, including mechanistic target of rapamycin, glycogen synthase kinase-3β, wnt/β-catenin, adenosine monophosophate-activated protein kinase, and sirtuins, related epigenetic changes, and preventing induction of immune regulatory cells (e.g., regulatory T cells, myeloid-derived suppressor cells) are powerful new approaches to improve vaccine responses. Interventions to favorably modulate these components have been studied primarily in oncology to induce efficient antitumor immune responses, often by potentiation of cancer vaccines. These agents include antibodies and a rapidly increasing number of small molecule drug classes that have contributed to the dramatic immune-based advances in treatment of cancer and other diseases. Because immune responses to malignancies and to Mtb share many similar mechanisms, studies to improve TB vaccine responses using interventions based on “immuno-oncology” are needed to guide possible repurposing. Understanding the regulation of immune cell functions appropriated by Mtb to promote the imbalance between protective and pathogenic immune responses may guide the development of innovative drug-based adjunct approaches to substantially enhance the clinical efficacy of TB vaccines.

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Glycogen Synthase Kinase-3β (GSK-3β) Inhibition Enhances Dendritic Cell-based Cancer Vaccine Potency via Suppression of Interferon-γ-induced Indoleamine 2,3-Dioxygenase Expression

Abstract: Background: IDO functions as a crucial mediator of tumor-mediated immune tolerance. Results: Here, we found that GSK-3␤-dependent IDO expression in the dendritic cell plays a role in anti-tumor activity via the regulation of CD8 ϩ T-cell proliferation and CTL activity.

Cited by 18 publications

References 26 publications

In vivo stepwise immunomodulation using chitosan nanoparticles as a platform nanotechnology for cancer immunotherapy

In vivo stepwise immunomodulation using chitosan nanoparticles as a platform nanotechnology for cancer immunotherapy

Platelet-activating Factor Mediates Endotoxin Tolerance by Regulating Indoleamine 2,3-Dioxygenase-dependent Expression of the Suppressor of Cytokine Signaling 3

Adjunct Strategies for Tuberculosis Vaccines: Modulating Key Immune Cell Regulatory Mechanisms to Potentiate Vaccination

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