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Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease, where even surgical resection and aggressive chemotherapy produce dismal outcomes. Immunotherapy is a promising alternative to conventional treatments, possessing the ability to elicit T cell-mediated killing of tumor cells and prevent disease recurrence. Immunotherapeutic approaches thus far have seen limited success in PDAC due to a poorly immunogenic and exceedingly immunosuppressive tumor microenvironment, which is enriched with dysfunctional and immunosuppressed antigen-presenting cells (APCs). We developed a highly potent immunostimulatory nanoparticle (immuno-NP) to activate and expand APCs in the tumor and induce local secretion of interferon β (IFNβ), which is a pro-inflammatory cytokine that plays a major role in APC recruitment. The effectiveness of the immuno-NP stems from its dual cargo of two synergistic immune modulators consisting of an agonist of the stimulator of interferon genes (STING) pathway and an agonist of the Toll-like receptor 4 (TLR4) pathway. We show the functional synergy of the dual-agonist cargo can be tweaked by adjusting the ratio of the two agonists loaded in the immuno-NP, leading to an increase in IFNβ production (11-fold) compared to any single agonist immuno-NP variant. Using the orthotopic murine Panc02 model of PDAC, we show that systemic administration allowed immuno-NPs to deposit into the perivascular regions of the tumor, which coincided with the APC-rich tumor areas leading to predominant uptake of immuno-NPs by APCs. The immuno-NPs were effectively taken up by a significant portion of dendritic cells in the tumor (>56%). This led to a significant expansion of APCs, resulting in an 11.5-fold increase of dendritic cells and infiltration of lymphocytes throughout the pancreatic tumor compared to untreated animals.

SUBMITTER: Lorkowski ME

PROVIDER: S-EPMC7906920 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors.

Lorkowski M E ME Atukorale P U PU Bielecki P A PA Tong K H KH Covarrubias G G Zhang Y Y Loutrianakis G G Moon T J TJ Santulli A R AR Becicka W M WM Karathanasis E E

Journal of controlled release : official journal of the Controlled Release Society 20201111

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease, where even surgical resection and aggressive chemotherapy produce dismal outcomes. Immunotherapy is a promising alternative to conventional treatments, possessing the ability to elicit T cell-mediated killing of tumor cells and prevent disease recurrence. Immunotherapeutic approaches thus far have seen limited success in PDAC due to a poorly immunogenic and exceedingly immunosuppressive tumor microenvironment, which is enrich ...[more]

PMID: 33188827

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Project description: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.SignificanceLoss 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.

Dataset Information

Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors.

Publications

Immunostimulatory nanoparticle incorporating two immune agonists for the treatment of pancreatic tumors.

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