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Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against
Juan R Cubillos-Ruiz1, Jason R Baird, Amelia J Tesone
1Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire, USA.
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.
Insights
This study demonstrates a novel nonviral approach to deliver microRNA-155 (miR-155) to ovarian cancer cells, transforming immunosuppressive cells into potent anti-tumor agents and halting cancer progression.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- MicroRNAs (miRNAs) offer novel cancer intervention strategies, but delivery challenges like low bioavailability and poor cellular uptake persist.
- Targeting tumor-associated dendritic cells (DCs) can enhance miRNA delivery and immune response.
Purpose of the Study:
- To develop a nonviral delivery system for the immunostimulatory miRNA miR-155 to ovarian cancer-associated dendritic cells (DCs).
- To investigate the in vivo processing and therapeutic efficacy of engineered miRNA mimetics.
Main Methods:
- Utilized nanoparticles to deliver pre-miRNA mimics to ovarian cancer-associated DCs, exploiting their enhanced endocytic activity.
- Analyzed in vivo processing of oligonucleotide duplexes and their impact on miR-155 activity and Argonaute (Ago) protein loading (Ago2, Ago4).
- Assessed genome-wide transcriptional changes and the functional transformation of DCs from immunosuppressive to immunostimulatory phenotypes.
Main Results:
- In vivo processing of pre-miRNA mimics significantly augmented miR-155 activity without saturating the RNA-induced silencing complex.
- Synthetic miR-155 preferentially loaded into Ago2 and Ago4, leading to the silencing of immunosuppressive mediators.
- Transformed tumor-infiltrating DCs exhibited potent anti-tumor responses, abrogating established ovarian cancer progression.
Conclusions:
- Nonviral delivery of miRNA mimetics is a feasible strategy to boost anti-tumor immunity.
- Engineered pre-miRNA mimics offer an effective platform for in vivo miRNA replenishment and cancer therapy.
- This approach provides a mechanistic rationale for clinical testing of nonviral miRNA-based cancer interventions.
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