A novel cancer therapy by skin delivery of indoleamine 2,3-dioxygenase siRNA

Meng Chi Yen, Chi Chen Lin, Yi Ling Chen, Shih Shien Huang, Huei Jiun Yang, Chih Peng Chang, Huan Yao Lei, Ming Derg Lai

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Abstract

Purpose: Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan, is a negative immune regulatory molecule of dendritic cells. IDO-expressing dendritic cells suppress Tcell responses and may be immunosuppressive in vivo. We hypothesized that silencing the IDO expression in skin dendritic cells in vivo could elicit antitumor activity in tumor-draining lymph nodes. Experimental Design: The efficiency of IDO-specific small interfering RNA (siRNA) was evaluated in vitro and in vivo. The therapeutic effect was evaluated in MBT-2 murine bladder tumor model and CT-26 colon tumor models. Results: IDO expression was down-regulated in CD11c-positive lymphocytes after IDO si RNA treatment. In vivo skin administration of IDO si RNA inhibited tumor growth and prolonged survival in both tumor models. The number of infiltrated T cells and neutrophils increased at tumor sites, which are correlated with therapeutic efficacy. The Tcells may be mainly responsible for the immunologic rejection because the effect was abolished by depletion of CD8-positiveTcells. Adoptive transfer of CD11c-positive dendritic cells from vaccinated mice delayed tumor progression. The cancer therapeutic effect was reproducibly observed with another IDO si RNA targeting at different site, suggesting the effect was not due to off-target effect. In a neu-overexpressing MBT-2 tumor model, IDO siRNA enhanced the therapeutic efficacy of Her2/Neu DNA vaccine. Down-regulation of IDO2, an IDO homologue, with siRNA also generated antitumor immunity in vivo. Conclusions: Antitumor immunity can be effectively elicited by physical delivery of siRNAs targeting immunoregulatory genes in skin dendritic cells in vivo, as shown by IDO and IDO2 in this report.

Original languageEnglish
Pages (from-to)641-649
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number2
DOIs
Publication statusPublished - 2009 Jan 15

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Skin Neoplasms
Small Interfering RNA
Neoplasms
Therapeutics
Dendritic Cells
Langerhans Cells
Therapeutic Uses
RNA
Immunity
DNA Vaccines
Gene Targeting
Adoptive Transfer
Immunosuppressive Agents
Urinary Bladder Neoplasms
Tryptophan
Colon
Neutrophils
Research Design
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Yen, Meng Chi ; Lin, Chi Chen ; Chen, Yi Ling ; Huang, Shih Shien ; Yang, Huei Jiun ; Chang, Chih Peng ; Lei, Huan Yao ; Lai, Ming Derg. / A novel cancer therapy by skin delivery of indoleamine 2,3-dioxygenase siRNA. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 2. pp. 641-649.
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abstract = "Purpose: Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan, is a negative immune regulatory molecule of dendritic cells. IDO-expressing dendritic cells suppress Tcell responses and may be immunosuppressive in vivo. We hypothesized that silencing the IDO expression in skin dendritic cells in vivo could elicit antitumor activity in tumor-draining lymph nodes. Experimental Design: The efficiency of IDO-specific small interfering RNA (siRNA) was evaluated in vitro and in vivo. The therapeutic effect was evaluated in MBT-2 murine bladder tumor model and CT-26 colon tumor models. Results: IDO expression was down-regulated in CD11c-positive lymphocytes after IDO si RNA treatment. In vivo skin administration of IDO si RNA inhibited tumor growth and prolonged survival in both tumor models. The number of infiltrated T cells and neutrophils increased at tumor sites, which are correlated with therapeutic efficacy. The Tcells may be mainly responsible for the immunologic rejection because the effect was abolished by depletion of CD8-positiveTcells. Adoptive transfer of CD11c-positive dendritic cells from vaccinated mice delayed tumor progression. The cancer therapeutic effect was reproducibly observed with another IDO si RNA targeting at different site, suggesting the effect was not due to off-target effect. In a neu-overexpressing MBT-2 tumor model, IDO siRNA enhanced the therapeutic efficacy of Her2/Neu DNA vaccine. Down-regulation of IDO2, an IDO homologue, with siRNA also generated antitumor immunity in vivo. Conclusions: Antitumor immunity can be effectively elicited by physical delivery of siRNAs targeting immunoregulatory genes in skin dendritic cells in vivo, as shown by IDO and IDO2 in this report.",
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A novel cancer therapy by skin delivery of indoleamine 2,3-dioxygenase siRNA. / Yen, Meng Chi; Lin, Chi Chen; Chen, Yi Ling; Huang, Shih Shien; Yang, Huei Jiun; Chang, Chih Peng; Lei, Huan Yao; Lai, Ming Derg.

In: Clinical Cancer Research, Vol. 15, No. 2, 15.01.2009, p. 641-649.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Lin, Chi Chen

AU - Chen, Yi Ling

AU - Huang, Shih Shien

AU - Yang, Huei Jiun

AU - Chang, Chih Peng

AU - Lei, Huan Yao

AU - Lai, Ming Derg

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N2 - Purpose: Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan, is a negative immune regulatory molecule of dendritic cells. IDO-expressing dendritic cells suppress Tcell responses and may be immunosuppressive in vivo. We hypothesized that silencing the IDO expression in skin dendritic cells in vivo could elicit antitumor activity in tumor-draining lymph nodes. Experimental Design: The efficiency of IDO-specific small interfering RNA (siRNA) was evaluated in vitro and in vivo. The therapeutic effect was evaluated in MBT-2 murine bladder tumor model and CT-26 colon tumor models. Results: IDO expression was down-regulated in CD11c-positive lymphocytes after IDO si RNA treatment. In vivo skin administration of IDO si RNA inhibited tumor growth and prolonged survival in both tumor models. The number of infiltrated T cells and neutrophils increased at tumor sites, which are correlated with therapeutic efficacy. The Tcells may be mainly responsible for the immunologic rejection because the effect was abolished by depletion of CD8-positiveTcells. Adoptive transfer of CD11c-positive dendritic cells from vaccinated mice delayed tumor progression. The cancer therapeutic effect was reproducibly observed with another IDO si RNA targeting at different site, suggesting the effect was not due to off-target effect. In a neu-overexpressing MBT-2 tumor model, IDO siRNA enhanced the therapeutic efficacy of Her2/Neu DNA vaccine. Down-regulation of IDO2, an IDO homologue, with siRNA also generated antitumor immunity in vivo. Conclusions: Antitumor immunity can be effectively elicited by physical delivery of siRNAs targeting immunoregulatory genes in skin dendritic cells in vivo, as shown by IDO and IDO2 in this report.

AB - Purpose: Indoleamine 2,3-dioxygenase (IDO), an enzyme that degrades tryptophan, is a negative immune regulatory molecule of dendritic cells. IDO-expressing dendritic cells suppress Tcell responses and may be immunosuppressive in vivo. We hypothesized that silencing the IDO expression in skin dendritic cells in vivo could elicit antitumor activity in tumor-draining lymph nodes. Experimental Design: The efficiency of IDO-specific small interfering RNA (siRNA) was evaluated in vitro and in vivo. The therapeutic effect was evaluated in MBT-2 murine bladder tumor model and CT-26 colon tumor models. Results: IDO expression was down-regulated in CD11c-positive lymphocytes after IDO si RNA treatment. In vivo skin administration of IDO si RNA inhibited tumor growth and prolonged survival in both tumor models. The number of infiltrated T cells and neutrophils increased at tumor sites, which are correlated with therapeutic efficacy. The Tcells may be mainly responsible for the immunologic rejection because the effect was abolished by depletion of CD8-positiveTcells. Adoptive transfer of CD11c-positive dendritic cells from vaccinated mice delayed tumor progression. The cancer therapeutic effect was reproducibly observed with another IDO si RNA targeting at different site, suggesting the effect was not due to off-target effect. In a neu-overexpressing MBT-2 tumor model, IDO siRNA enhanced the therapeutic efficacy of Her2/Neu DNA vaccine. Down-regulation of IDO2, an IDO homologue, with siRNA also generated antitumor immunity in vivo. Conclusions: Antitumor immunity can be effectively elicited by physical delivery of siRNAs targeting immunoregulatory genes in skin dendritic cells in vivo, as shown by IDO and IDO2 in this report.

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