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

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

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Dendritic cell (DC)-based cancer vaccines have become important as an immunotherapeutics in generating anti-tumor immune responses. Due to a short lifespan of DCs, however, clinical application of current DC vaccines has been limited. Recently, activation of AKT/protein kinase B (PKB), a major effector of phosphatidylinositol 3-kinase (PI3K), has been reported as a critical factor in both activation and survival of DCs. We here improved the potency of a DC vaccine with a small interfering RNA (siRNA) targeting phosphatase and tensin homologue (PTEN), which is known to be a central negative regulator of the PI3K/AKT signal transduction cascade. Down-regulation of PTEN in DCs resulted in AKT dependent maturation, which in turn caused a significant up-regulation of surface expression in co-stimulatory molecules and the chemokine receptor, CCR7, leading to an increase of in vitro T cell activation activity and in vivo migration to a draining lymph node, respectively. Moreover, these PTEN siRNA-transfected DCs (DC/siPTEN) acquired an increased survival from the apoptotic death caused by GM-CSF deprivation or antigen-specific CD8+ T cell killing. Most importantly, DC/siPTEN generated more tumor antigen-specific CD8+ T cells and stronger anti-tumor effects in vaccinated mice than did control DCs (DC/siGFP). Thus, our data indicate that manipulation of the PI3K/AKT pathway via siRNA system could improve the efficacy of a DC-based tumor vaccine.

Original languageEnglish
Pages (from-to)47-54
Number of pages8
JournalImmunology Letters
Volume134
Issue number1
DOIs
Publication statusPublished - 2010 Nov 30

Fingerprint

Vaccine Potency
Phosphatidylinositol 3-Kinase
Phosphoric Monoester Hydrolases
Dendritic Cells
Small Interfering RNA
Cancer Vaccines
T-Lymphocytes
Vaccines
CD8 Antigens
Proto-Oncogene Proteins c-akt
Chemokine Receptors
Neoplasm Antigens
Granulocyte-Macrophage Colony-Stimulating Factor
Tensins
Signal Transduction
Neoplasms
Up-Regulation
Down-Regulation
Lymph Nodes

Keywords

  • AKT
  • Dendritic cell
  • Immunotherapy
  • PI3K
  • PTEN
  • SiRNA

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

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, Ye Hyeon; Choi, Eun Young; Kim, Jin Seok; Lee, Kyung-Mi; Kim, Tae Woo.

In: Immunology Letters, Vol. 134, No. 1, 30.11.2010, p. 47-54.

Research output: Contribution to journalArticle

Kim, JH, Kang, TH, Noh, KH, Kim, SH, Lee, YH, Kim, KW, Bae, HC, Ahn, YH, Choi, EY, Kim, JS, Lee, K-M & Kim, TW 2010, 'Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN', Immunology Letters, vol. 134, no. 1, pp. 47-54. https://doi.org/10.1016/j.imlet.2010.08.008
Kim, Jin Hee ; Kang, Tae Heung ; Noh, Kyung Hee ; Kim, Seok Ho ; Lee, Young Ho ; Kim, Keon Woo ; Bae, Hyun Cheol ; Ahn, Ye Hyeon ; Choi, Eun Young ; Kim, Jin Seok ; Lee, Kyung-Mi ; Kim, Tae Woo. / Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN. In: Immunology Letters. 2010 ; Vol. 134, No. 1. pp. 47-54.
@article{cea8a898aada4e4382fc6e214f341145,
title = "Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN",
abstract = "Dendritic cell (DC)-based cancer vaccines have become important as an immunotherapeutics in generating anti-tumor immune responses. Due to a short lifespan of DCs, however, clinical application of current DC vaccines has been limited. Recently, activation of AKT/protein kinase B (PKB), a major effector of phosphatidylinositol 3-kinase (PI3K), has been reported as a critical factor in both activation and survival of DCs. We here improved the potency of a DC vaccine with a small interfering RNA (siRNA) targeting phosphatase and tensin homologue (PTEN), which is known to be a central negative regulator of the PI3K/AKT signal transduction cascade. Down-regulation of PTEN in DCs resulted in AKT dependent maturation, which in turn caused a significant up-regulation of surface expression in co-stimulatory molecules and the chemokine receptor, CCR7, leading to an increase of in vitro T cell activation activity and in vivo migration to a draining lymph node, respectively. Moreover, these PTEN siRNA-transfected DCs (DC/siPTEN) acquired an increased survival from the apoptotic death caused by GM-CSF deprivation or antigen-specific CD8+ T cell killing. Most importantly, DC/siPTEN generated more tumor antigen-specific CD8+ T cells and stronger anti-tumor effects in vaccinated mice than did control DCs (DC/siGFP). Thus, our data indicate that manipulation of the PI3K/AKT pathway via siRNA system could improve the efficacy of a DC-based tumor vaccine.",
keywords = "AKT, Dendritic cell, Immunotherapy, PI3K, PTEN, SiRNA",
author = "Kim, {Jin Hee} and Kang, {Tae Heung} and Noh, {Kyung Hee} and Kim, {Seok Ho} and Lee, {Young Ho} and Kim, {Keon Woo} and Bae, {Hyun Cheol} and Ahn, {Ye Hyeon} and Choi, {Eun Young} and Kim, {Jin Seok} and Kyung-Mi Lee and Kim, {Tae Woo}",
year = "2010",
month = "11",
day = "30",
doi = "10.1016/j.imlet.2010.08.008",
language = "English",
volume = "134",
pages = "47--54",
journal = "Immunology Letters",
issn = "0165-2478",
publisher = "Elsevier",
number = "1",

}

TY - JOUR

T1 - Enhancement of DC vaccine potency by activating the PI3K/AKT pathway with a small interfering RNA targeting PTEN

AU - Kim, Jin Hee

AU - Kang, Tae Heung

AU - Noh, Kyung Hee

AU - Kim, Seok Ho

AU - Lee, Young Ho

AU - Kim, Keon Woo

AU - Bae, Hyun Cheol

AU - Ahn, Ye Hyeon

AU - Choi, Eun Young

AU - Kim, Jin Seok

AU - Lee, Kyung-Mi

AU - Kim, Tae Woo

PY - 2010/11/30

Y1 - 2010/11/30

N2 - Dendritic cell (DC)-based cancer vaccines have become important as an immunotherapeutics in generating anti-tumor immune responses. Due to a short lifespan of DCs, however, clinical application of current DC vaccines has been limited. Recently, activation of AKT/protein kinase B (PKB), a major effector of phosphatidylinositol 3-kinase (PI3K), has been reported as a critical factor in both activation and survival of DCs. We here improved the potency of a DC vaccine with a small interfering RNA (siRNA) targeting phosphatase and tensin homologue (PTEN), which is known to be a central negative regulator of the PI3K/AKT signal transduction cascade. Down-regulation of PTEN in DCs resulted in AKT dependent maturation, which in turn caused a significant up-regulation of surface expression in co-stimulatory molecules and the chemokine receptor, CCR7, leading to an increase of in vitro T cell activation activity and in vivo migration to a draining lymph node, respectively. Moreover, these PTEN siRNA-transfected DCs (DC/siPTEN) acquired an increased survival from the apoptotic death caused by GM-CSF deprivation or antigen-specific CD8+ T cell killing. Most importantly, DC/siPTEN generated more tumor antigen-specific CD8+ T cells and stronger anti-tumor effects in vaccinated mice than did control DCs (DC/siGFP). Thus, our data indicate that manipulation of the PI3K/AKT pathway via siRNA system could improve the efficacy of a DC-based tumor vaccine.

AB - Dendritic cell (DC)-based cancer vaccines have become important as an immunotherapeutics in generating anti-tumor immune responses. Due to a short lifespan of DCs, however, clinical application of current DC vaccines has been limited. Recently, activation of AKT/protein kinase B (PKB), a major effector of phosphatidylinositol 3-kinase (PI3K), has been reported as a critical factor in both activation and survival of DCs. We here improved the potency of a DC vaccine with a small interfering RNA (siRNA) targeting phosphatase and tensin homologue (PTEN), which is known to be a central negative regulator of the PI3K/AKT signal transduction cascade. Down-regulation of PTEN in DCs resulted in AKT dependent maturation, which in turn caused a significant up-regulation of surface expression in co-stimulatory molecules and the chemokine receptor, CCR7, leading to an increase of in vitro T cell activation activity and in vivo migration to a draining lymph node, respectively. Moreover, these PTEN siRNA-transfected DCs (DC/siPTEN) acquired an increased survival from the apoptotic death caused by GM-CSF deprivation or antigen-specific CD8+ T cell killing. Most importantly, DC/siPTEN generated more tumor antigen-specific CD8+ T cells and stronger anti-tumor effects in vaccinated mice than did control DCs (DC/siGFP). Thus, our data indicate that manipulation of the PI3K/AKT pathway via siRNA system could improve the efficacy of a DC-based tumor vaccine.

KW - AKT

KW - Dendritic cell

KW - Immunotherapy

KW - PI3K

KW - PTEN

KW - SiRNA

UR - http://www.scopus.com/inward/record.url?scp=78049306941&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78049306941&partnerID=8YFLogxK

U2 - 10.1016/j.imlet.2010.08.008

DO - 10.1016/j.imlet.2010.08.008

M3 - Article

VL - 134

SP - 47

EP - 54

JO - Immunology Letters

JF - Immunology Letters

SN - 0165-2478

IS - 1

ER -