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Nanoparticle Delivery of Immunostimulatory Alu RNA for Cancer Immunotherapy.
Garland, Kyle M; Kwiatkowski, Alexander J; Tossberg, John T; Crooke, Philip S; Aune, Thomas M; Wilson, John T.
Affiliation
  • Garland KM; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee.
  • Kwiatkowski AJ; Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, Tennessee.
  • Tossberg JT; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Crooke PS; Department of Mathematics, Vanderbilt University, Nashville, Tennessee.
  • Aune TM; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Wilson JT; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Cancer Res Commun ; 3(9): 1800-1809, 2023 09.
Article in En | MEDLINE | ID: mdl-37691856
ABSTRACT
It was recently found that patients with relapsing remitting multiple sclerosis exhibit widespread loss of adenosine-to-inosine (A-to-I) RNA editing, which contributes to the accumulation of immunostimulatory double-stranded Alu RNA in circulating leukocytes and an attendant increase in levels of proinflammatory cytokines (e.g., type I IFNs). A specific Alu RNA (i.e., AluJb RNA) was implicated in activating multiple RNA-sensing pathways and found to be a potent innate immune agonist. Here, we have performed a bioinformatic analysis of A-to-I RNA editing in human melanoma samples and determined that pre-therapy levels of A-to-I RNA editing negatively correlate with survival times, suggesting that an accumulation of endogenous double-stranded Alu RNA might contribute to cancer patient survival. Furthermore, we demonstrated that immunostimulatory Alu RNA can be leveraged pharmacologically for cancer immunotherapy. AluJb RNA was in vitro transcribed and then formulated with endosome-destabilizing polymer nanoparticles to improve intracellular delivery of the RNA and enable activation of RNA-sensing pathways. AluJb RNA/polymer complexes (i.e., Alu-NPs) were engineered to form colloidally stable nanoparticles that exhibited immunostimulatory activity in vitro and in vivo. Finally, the therapeutic potential of Alu-NPs for the treatment of cancer was demonstrated by attenuated tumor growth and prolonged survival in the B16.F10 murine melanoma tumor model. Thus, these data collectively implicate intratumoral Alu RNA as a potentiator of antitumor innate immunity and identify AluJb RNA as a novel nucleic acid immunotherapeutic for cancer.

Significance:

Loss of A-to-I editing leads to accumulation of unedited Alu RNAs that activate innate immunity via RNA-sensing pattern recognition receptors. When packaged into endosome-releasing polymer nanoparticles, AluJB RNA becomes highly immunostimulatory and can be used pharmacologically to inhibit tumor growth in mouse melanoma models. These findings identify Alu RNAs as a new class of nucleic acid innate immune agonists for cancer immunotherapy.
Subject(s)

Full text: 1 Database: MEDLINE Main subject: Nucleic Acids / Melanoma Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cancer Res Commun Year: 2023 Type: Article

Full text: 1 Database: MEDLINE Main subject: Nucleic Acids / Melanoma Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: Cancer Res Commun Year: 2023 Type: Article