Year: 2021
Type: article
Abstract: When compartmentally mislocalized within cells, nucleic acids can be exceptionally immunostimulatory and can even trigger the immune-mediated elimination of cancer. Specifically, the accumulation of double-stranded DNA in the cytosol can efficiently promote antitumor immunity by activating the cGAMP synthase (cGAS) / stimulator of interferon genes (STING) cellular signaling pathway. Targeting this cytosolic DNA sensing pathway with interferon stimulatory DNA (ISD) is therefore an attractive immunotherapeutic strategy for the treatment of cancer. However, the therapeutic activity of ISD is limited by several drug delivery barriers, including susceptibility to deoxyribonuclease degradation, poor cellular uptake, and inefficient cytosolic delivery. Here, we describe the development of a nucleic acid immunotherapeutic, NanoISD, which overcomes critical delivery barriers that limit the activity of ISD and thereby promotes antitumor immunity through the pharmacological activation of cGAS at the forefront of the STING pathway. NanoISD is a nanoparticle formulation that has been engineered to confer deoxyribonuclease resistance, enhance cellular uptake, and promote endosomal escape of ISD into the cytosol, resulting in potent activation of the STING pathway via cGAS. NanoISD mediates the local production of proinflammatory cytokines via STING signaling. Accordingly, the intratumoral administration of NanoISD induces the infiltration of natural killer cells and T lymphocytes into murine tumors. The therapeutic efficacy of NanoISD is demonstrated in preclinical tumor models by attenuated tumor growth, prolonged survival, and an improved response to immune checkpoint blockade therapy.
Source: Frontiers in Immunology
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,950
Funders: National Science Foundation, American Association for Cancer Research, American Cancer Society, Entertainment Industry Foundation, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Stand Up To Cancer, Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt University, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Division of Graduate Education, Division of Chemical, Bioengineering, Environmental, and Transport Systems, Congressionally Directed Medical Research Programs
Awards: Graduate Research Fellowship Program (GRFP), G187284979, CAREER: Engineering Polymeric Nanomaterials for Programming Innate Immunity, G2272150506, G2648632450, G3334359601, Inside-Out Immunotherapy: Preventing Metastatic Breast Cancer Recurrence via Nanoparticle-Directed Modulation of the Tumor Microenvironment, G4863672648, Graduate Research Fellowship Program (GRFP), G5760731592, SPORE in Breast Cancer, G7279127475, G7504319281, Molecular and Cellular Basis for Digestive Diseases, Cancer Center Support Grant, Deciphering Post-transcriptional Gene Regulatory Networks During Periods of Host-Pathogen Interaction and Innate Immune Activation
OpenAlex ID: W3215551771