Abstract P2-02-02: CHEMOTHERAPEUTIC TOPOISOMERASE 2 POISONS GENERATE TREX1 RESISTANT DNA FRAGMENTS THAT INDUCE A POTENT cGAS/STING RESPONSE

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Abstract Tumours with genomic instability display enhanced immunogenicity and potential for response to immune checkpoint blockade (ICB). Interestingly, chemotherapy mediated DNA damage can also stimulate the immune system through activation of the cGAS/STING innate immune pathway and therefore, improve clinical outcomes in combination with ICB. Here we set out to compare the ability of classically used chemotherapies to activate innate immunity, as well as characterise the mechanism(s) behind it. We identified topoisomerase 2 (TOP2) poisons, such as anthracyclines, as the most effective activators of cGAS/STING, leading to a potent type I interferon response. Mechanistically, we demonstrate that abortive TOP2cc repair intermediates (dsDNA fragments containing 5’-phosphotyrosyl residues) get encapsulated within micronuclei and activate cGAS, which can be blocked with antimitotic agents (e.g. taxanes). Crucially, we discovered that these 5’-phosphotyrosyl linked fragments are resistant to nuclease degradation by the cytoplasmic nuclease TREX1, which stabilises them, resulting in robust cGAS/STING mediated inflammation. Finally, using in vivo modelling, we confirmed that Top2 poisons enhance anti-tumour responses to ICB in comparison to taxanes. In line with this, using pre and on-treatment breast tumour biopsies, we have shown that anthracycline-based chemotherapy induces a robust type I interferon response in breast tumours, driving tumour lymphocytic infiltration. Moreover, following anthracycline treatment with taxane treatment results in supression of lymphocytic infiltration in these same tumours. Collectively, our findings reveal that TOP2 poison mediated DNA lesions enhance cGAS substrate availability by impairing cytoplasmic dsDNA degradation, highlighting their ability to drive anti-tumour immune responses and enhance the therapeutic efficacy of ICB. Citation Format: Kienan Savage, Eliana M. Barros, Richard D.A. Wilkinson, Guido Zagnoli-Viera, Stuart A. McIntosh, Katrina M. Lappin, Oliver Barker, Ieuan L. Morgan, Eileen E. Parkes, Marc A. Fuchs, Nuala McCabe, Roger A. Greenberg, Tim Harrison, Keith W. Caldecott, Richard D. Kennedy. CHEMOTHERAPEUTIC TOPOISOMERASE 2 POISONS GENERATE TREX1 RESISTANT DNA FRAGMENTS THAT INDUCE A POTENT cGAS/STING RESPONSE [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-02-02.

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