Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer

Juan R. Cubillos-Ruiz, Jason R. Baird, Amelia J. Tesone, Melanie R. Rutkowski, Uciane K. Scarlett, Ana L. Camposeco-Jacobs, Jorge Anadon-Arnillas, Noah M. Harwood, Murray Korc, Steven N. Fiering, Lorenzo F. Sempere, Jose R. Conejo-Garcia

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

Modulating the activity of miRNAs provides opportunities for novel cancer interventions. However, low bioavailability and poor cellular uptake are major challenges for delivering miRNA mimetics specifically to tumor cells. Here, we took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated dendritic cells (DC) to selectively supplement the immunostimulatory miRNA miR-155. In vivo processing of nanoparticles carrying oligonucleotide duplexes mimicking the bulged structure of endogenous pre-miRNA (but not siRNA-like oligonucleotides) dramatically augmented miR-155 activity without saturating the RNA-induced silencing complex. Endogenous processing of synthetic miR-155 favored Ago2 and, to a lesser extent, Ago4 loading, resulting in genome-wide transcriptional changes that included silencing of multiple immunosuppressive mediators. Correspondingly, tumor-infiltrating DCs were transformed from immunosuppressive to highly immunostimulatory cells capable of triggering potent antitumor responses that abrogated the progression of established ovarian cancers. Our results show both the feasibility and therapeutic potential of supplementing/replenishing miRNAs in vivo using nonviral approaches to boost protective immunity against lethal tumors. Thus, we provide a platform, an optimized design, and a mechanistic rationale for the clinical testing of nonviral miRNA mimetics.

Original languageEnglish (US)
Pages (from-to)1683-1693
Number of pages11
JournalCancer Research
Volume72
Issue number7
DOIs
StatePublished - Apr 1 2012

Fingerprint

MicroRNAs
Ovarian Neoplasms
Dendritic Cells
Immunity
Neoplasms
Immunosuppressive Agents
Oligonucleotides
RNA-Induced Silencing Complex
Nanoparticles
Small Interfering RNA
Biological Availability
Genome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Cubillos-Ruiz, J. R., Baird, J. R., Tesone, A. J., Rutkowski, M. R., Scarlett, U. K., Camposeco-Jacobs, A. L., ... Conejo-Garcia, J. R. (2012). Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer. Cancer Research, 72(7), 1683-1693. https://doi.org/10.1158/0008-5472.CAN-11-3160

Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer. / Cubillos-Ruiz, Juan R.; Baird, Jason R.; Tesone, Amelia J.; Rutkowski, Melanie R.; Scarlett, Uciane K.; Camposeco-Jacobs, Ana L.; Anadon-Arnillas, Jorge; Harwood, Noah M.; Korc, Murray; Fiering, Steven N.; Sempere, Lorenzo F.; Conejo-Garcia, Jose R.

In: Cancer Research, Vol. 72, No. 7, 01.04.2012, p. 1683-1693.

Research output: Contribution to journalArticle

Cubillos-Ruiz, JR, Baird, JR, Tesone, AJ, Rutkowski, MR, Scarlett, UK, Camposeco-Jacobs, AL, Anadon-Arnillas, J, Harwood, NM, Korc, M, Fiering, SN, Sempere, LF & Conejo-Garcia, JR 2012, 'Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer', Cancer Research, vol. 72, no. 7, pp. 1683-1693. https://doi.org/10.1158/0008-5472.CAN-11-3160
Cubillos-Ruiz JR, Baird JR, Tesone AJ, Rutkowski MR, Scarlett UK, Camposeco-Jacobs AL et al. Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer. Cancer Research. 2012 Apr 1;72(7):1683-1693. https://doi.org/10.1158/0008-5472.CAN-11-3160
Cubillos-Ruiz, Juan R. ; Baird, Jason R. ; Tesone, Amelia J. ; Rutkowski, Melanie R. ; Scarlett, Uciane K. ; Camposeco-Jacobs, Ana L. ; Anadon-Arnillas, Jorge ; Harwood, Noah M. ; Korc, Murray ; Fiering, Steven N. ; Sempere, Lorenzo F. ; Conejo-Garcia, Jose R. / Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer. In: Cancer Research. 2012 ; Vol. 72, No. 7. pp. 1683-1693.
@article{12a71c60dc514b8396f032a4a0dd4383,
title = "Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer",
abstract = "Modulating the activity of miRNAs provides opportunities for novel cancer interventions. However, low bioavailability and poor cellular uptake are major challenges for delivering miRNA mimetics specifically to tumor cells. Here, we took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated dendritic cells (DC) to selectively supplement the immunostimulatory miRNA miR-155. In vivo processing of nanoparticles carrying oligonucleotide duplexes mimicking the bulged structure of endogenous pre-miRNA (but not siRNA-like oligonucleotides) dramatically augmented miR-155 activity without saturating the RNA-induced silencing complex. Endogenous processing of synthetic miR-155 favored Ago2 and, to a lesser extent, Ago4 loading, resulting in genome-wide transcriptional changes that included silencing of multiple immunosuppressive mediators. Correspondingly, tumor-infiltrating DCs were transformed from immunosuppressive to highly immunostimulatory cells capable of triggering potent antitumor responses that abrogated the progression of established ovarian cancers. Our results show both the feasibility and therapeutic potential of supplementing/replenishing miRNAs in vivo using nonviral approaches to boost protective immunity against lethal tumors. Thus, we provide a platform, an optimized design, and a mechanistic rationale for the clinical testing of nonviral miRNA mimetics.",
author = "Cubillos-Ruiz, {Juan R.} and Baird, {Jason R.} and Tesone, {Amelia J.} and Rutkowski, {Melanie R.} and Scarlett, {Uciane K.} and Camposeco-Jacobs, {Ana L.} and Jorge Anadon-Arnillas and Harwood, {Noah M.} and Murray Korc and Fiering, {Steven N.} and Sempere, {Lorenzo F.} and Conejo-Garcia, {Jose R.}",
year = "2012",
month = "4",
day = "1",
doi = "10.1158/0008-5472.CAN-11-3160",
language = "English (US)",
volume = "72",
pages = "1683--1693",
journal = "Cancer Research",
issn = "0008-5472",
number = "7",

}

TY - JOUR

T1 - Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer

AU - Cubillos-Ruiz, Juan R.

AU - Baird, Jason R.

AU - Tesone, Amelia J.

AU - Rutkowski, Melanie R.

AU - Scarlett, Uciane K.

AU - Camposeco-Jacobs, Ana L.

AU - Anadon-Arnillas, Jorge

AU - Harwood, Noah M.

AU - Korc, Murray

AU - Fiering, Steven N.

AU - Sempere, Lorenzo F.

AU - Conejo-Garcia, Jose R.

PY - 2012/4/1

Y1 - 2012/4/1

N2 - Modulating the activity of miRNAs provides opportunities for novel cancer interventions. However, low bioavailability and poor cellular uptake are major challenges for delivering miRNA mimetics specifically to tumor cells. Here, we took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated dendritic cells (DC) to selectively supplement the immunostimulatory miRNA miR-155. In vivo processing of nanoparticles carrying oligonucleotide duplexes mimicking the bulged structure of endogenous pre-miRNA (but not siRNA-like oligonucleotides) dramatically augmented miR-155 activity without saturating the RNA-induced silencing complex. Endogenous processing of synthetic miR-155 favored Ago2 and, to a lesser extent, Ago4 loading, resulting in genome-wide transcriptional changes that included silencing of multiple immunosuppressive mediators. Correspondingly, tumor-infiltrating DCs were transformed from immunosuppressive to highly immunostimulatory cells capable of triggering potent antitumor responses that abrogated the progression of established ovarian cancers. Our results show both the feasibility and therapeutic potential of supplementing/replenishing miRNAs in vivo using nonviral approaches to boost protective immunity against lethal tumors. Thus, we provide a platform, an optimized design, and a mechanistic rationale for the clinical testing of nonviral miRNA mimetics.

AB - Modulating the activity of miRNAs provides opportunities for novel cancer interventions. However, low bioavailability and poor cellular uptake are major challenges for delivering miRNA mimetics specifically to tumor cells. Here, we took advantage of the spontaneous enhanced endocytic activity of ovarian cancer-associated dendritic cells (DC) to selectively supplement the immunostimulatory miRNA miR-155. In vivo processing of nanoparticles carrying oligonucleotide duplexes mimicking the bulged structure of endogenous pre-miRNA (but not siRNA-like oligonucleotides) dramatically augmented miR-155 activity without saturating the RNA-induced silencing complex. Endogenous processing of synthetic miR-155 favored Ago2 and, to a lesser extent, Ago4 loading, resulting in genome-wide transcriptional changes that included silencing of multiple immunosuppressive mediators. Correspondingly, tumor-infiltrating DCs were transformed from immunosuppressive to highly immunostimulatory cells capable of triggering potent antitumor responses that abrogated the progression of established ovarian cancers. Our results show both the feasibility and therapeutic potential of supplementing/replenishing miRNAs in vivo using nonviral approaches to boost protective immunity against lethal tumors. Thus, we provide a platform, an optimized design, and a mechanistic rationale for the clinical testing of nonviral miRNA mimetics.

UR - http://www.scopus.com/inward/record.url?scp=84859386994&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859386994&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-11-3160

DO - 10.1158/0008-5472.CAN-11-3160

M3 - Article

C2 - 22307839

AN - SCOPUS:84859386994

VL - 72

SP - 1683

EP - 1693

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 7

ER -