DNA-Containing Exosomes Derived from Cancer Cells Treated with Topotecan Activate a STING-Dependent Pathway and...

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Danger-associated molecular patterns (DAMPs) from dying cells promote inflammation and anti-tumor immunity.
• Topotecan (TPT), a topoisomerase I inhibitor, is an anti-cancer agent.

Purpose of the Study:

• To investigate whether TPT treatment of breast cancer cells induces DAMP secretion.
• To determine if TPT-induced DAMPs activate dendritic cells (DCs) and potentiate anti-tumor immune responses.
• To elucidate the role of STING (STimulator of INterferon Genes) in TPT-mediated anti-tumor effects.

Main Methods:

• Treatment of breast cancer cells with TPT.
• Analysis of DAMP secretion and DC activation/cytokine production.
• Assessment of tumor growth, immune cell infiltration (DCs, CD8+ T cells) in tumor-bearing mice.
• Evaluation of TPT effects in STING-deficient mice.
• Characterization of exosomes released from TPT-treated cancer cells and their DNA content.
• Investigation of DC activation by TPT-derived exosomes via STING signaling.

Main Results:

• TPT treatment induced DAMP secretion from breast cancer cells, leading to DC activation and cytokine production.
• TPT administration inhibited tumor growth in mice, correlating with increased infiltration of activated DCs and CD8+ T cells.
• These anti-tumor effects were abolished in STING-deficient mice.
• TPT-treated cancer cells released exosomes containing DNA, which activated DCs through STING signaling.

Conclusions:

• TPT acts as an immunogenic cell death inducer, releasing tumor-derived DNA via exosomes.
• This DNA activates DCs through the STING pathway, driving a potent anti-tumor immune response.
• The findings reveal a STING-dependent mechanism linking TPT treatment to adaptive anti-tumor immunity.