Efficient DNA Repair Mitigates Replication Stress Resulting in Less Immunogenic Cytosolic DNA in Radioresistant Breast Cancer Stem Cells

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

Abstract

Cancer stem cells (CSCs) are a major cause of tumor therapy failure. This is mainly attributed to increased DNA repair capacity and immune escape. Recent studies have shown that functional DNA repair via homologous recombination (HR) prevents radiation-induced accumulation of DNA in the cytoplasm, thereby inhibiting the intracellular immune response. However, it is unclear whether CSCs can suppress radiation-induced cytoplasmic dsDNA formation. Here, we show that the increased radioresistance of ALDH1-positive breast cancer stem cells (BCSCs) in S phase is mediated by both enhanced DNA double-strand break repair and improved replication fork protection due to HR. Both HR-mediated processes lead to suppression of radiation-induced replication stress and consequently reduction of cytoplasmic dsDNA. The amount of cytoplasmic dsDNA correlated significantly with BCSC content (p=0.0002). This clearly indicates that HR-dependent avoidance of radiation-induced replication stress mediates radioresistance and contributes to its immune evasion. Consistent with this, enhancement of replication stress by inhibition of ataxia telangiectasia and RAD3 related (ATR) resulted in significant radiosensitization (SER37 increase 1.7-2.8 Gy, p<0.0001). Therefore, disruption of HR-mediated processes, particularly in replication, opens a CSC-specific radiosensitization option by enhancing their intracellular immune response.

Details

Original languageEnglish
Article number765284
JournalFrontiers in immunology
Volume13
Publication statusPublished - 25 Feb 2022
Peer-reviewedYes

External IDs

PubMedCentral PMC8913591
Scopus 85126181105
WOS 000770697400001
unpaywall 10.3389/fimmu.2022.765284
Mendeley f309a178-385e-3695-897f-a777f9ba8873

Keywords

Sustainable Development Goals

ASJC Scopus subject areas

Keywords

  • ATR inhibition, DNA repair, breast cancer stem cells (BCSCs), cellular immuneresponse, homologous recombination, immunogenic cytosolic dsDNA, radioresistance, replication stress

Library keywords