Pharmacological Activation of cGAS for Cancer Immunotherapy

Front Immunol. 2021 Nov 26;12:753472. doi: 10.3389/fimmu.2021.753472. eCollection 2021.

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.

Keywords: cGAS/STING pathway; cancer; endosomal escape; immunotherapy; innate immune agonist; intratumoral; nanoparticles; nucleic acid therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Colonic Neoplasms / therapy
  • Cytokines / biosynthesis
  • Cytokines / genetics
  • DNA / administration & dosage
  • DNA / chemical synthesis
  • DNA / pharmacology
  • DNA / therapeutic use*
  • Drug Delivery Systems*
  • Drug Screening Assays, Antitumor
  • Endosomes / physiology
  • Female
  • Humans
  • Immunotherapy / methods
  • Killer Cells, Natural / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mammary Neoplasms, Experimental / therapy
  • Melanoma, Experimental / therapy
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Nanoparticles / administration & dosage
  • Nanoparticles / therapeutic use*
  • Neoplasms / immunology
  • Nucleotidyltransferases / drug effects*
  • Signal Transduction / drug effects
  • T-Lymphocyte Subsets / immunology
  • Thionucleotides / pharmacology
  • Tumor Microenvironment / drug effects

Substances

  • Cytokines
  • Membrane Proteins
  • STING1 protein, human
  • Sting1 protein, mouse
  • Thionucleotides
  • DNA
  • Nucleotidyltransferases
  • cGAS protein, human
  • cGAS protein, mouse