2. Academic Validation
  3. Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity

Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity

  • Cell Rep. 2025 Feb 25;44(2):115177. doi: 10.1016/j.celrep.2024.115177.
Shayla R Mosley 1,  Angie Chen 2,  David N W Doell 2,  Siwon Choi 2,  Courtney Mowat 2,  Felix Meier-Stephenson 3,  Vanessa Meier-Stephenson 3,  Kristi Baker 4
Affiliations

Affiliations

  • 1 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada. Electronic address: mosley@ualberta.ca.
  • 2 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
  • 3 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2R3, Canada.
  • 4 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2R3, Canada. Electronic address: kbaker2@alberta.ca.
PMID: 39864057 DOI: 10.1016/j.celrep.2024.115177
Abstract

Patients with colorectal cancers (CRCs) that have microsatellite instability (MSI) (MSI CRCs) face a better prognosis than those with the more common chromosomal instability (CIN) subtype (CIN CRCs) due to improved T cell-mediated anti-tumor immune responses. Previous investigations identified the cytosolic DNA (cyDNA) sensor STING as necessary for chemokine-mediated T cell recruitment in MSI CRCs. Here, we find that cyDNA from MSI CRC cells is inherently more capable of inducing STING activation and improves cytotoxic T cell activation by dendritic cells (DCs). Sequencing indicates that MSI cyDNA is enriched in microsatellites, which, upon DC uptake, induce anti-tumor immunity in a manner consistent with clinical MSI CRCs. DNA-damaging therapies also modulate cyDNA stimulation capacity, with radiation inducing larger cyDNA sizes and increased mitochondrial DNA content. Identifying highly stimulatory endogenous cyDNAs such as those in MSI CRCs will allow for optimized development of DNA-based STING agonist therapies to improve the responses of CIN CRCs with CIN to immunotherapies.

Keywords

CP: Cancer; CP: Immunology; DNA repair; anti-tumor immunity; cGAS/STING signaling; colorectal cancer; dendritic cells; genomic instability.

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