Topoisomerase II inhibitors enhance STING-dependent cytokine release and immune checkpoint activation

Research output: Contribution to conferenceAbstractpeer-review

Abstract

A significant proportion of breast cancers exhibit a DNA double strand break repair (DSBR) deficiency and are genomically unstable. Evidence suggests that genomic instability correlates with response to immune checkpoint inhibition. This has been attributed to accumulation of mutations resulting in neo-antigen expression, leading to an immune response, which is inhibited by immune checkpointing proteins such as PD-L1. However, we recently reported an additional mechanism for immune activation in DSBR-deficient breast cancers. We reported that cytoplasmic DNA resulting from defective DNA repair triggers the cGAS/STING pathway, causing IRF3 activation and switching on an immune transcriptional cascade. Furthermore, we have developed and validated a gene expression signature termed the DNA Damage Immune Response (DDIR) assay that identifies a subset of breast cancer patients with activation of this immune transcriptional cascade. The signature has been validated in several independent datasets, including our recent prospective Neo-DDRD clinical trial. Additionally, we have found that this signature is “switched on” in response to DNA damage, suggesting that therapeutic challenge with DNA-damaging chemotherapies may sensitise tumours to immune checkpoint blockade.
To examine this further, we assessed induction of two key DDIR signature chemokines CXCL10 and CCL5 following treatment with IC30 doses of various chemotherapies that induce different types of DNA damage. CXCL10/ CCL5 induction was greatest following treatment with the Topo-II inhibitors Doxorubicin and Etoposide and both of these drugs resulted in the greatest release of dsDNA into the cytoplasm. In keeping with this, Topo-II inhibitor induced CXCL10/CCL5 induction was dependent on micronuclei formation and cGAS/STING pathway activation and results in the induction of multiple immune checkpoint genes. Finally, we show that treatment of breast cancer patients with neoadjuvant epirubicin results in chemokine induction. This supports the use of Topo-II inhibitors to convert immune “cold” tumours to “hot” tumours, suggesting rational combinations with immune checkpoint inhibitors.
Original languageEnglish
Publication statusPublished - 15 Apr 2019
Event31st International Association for
Breast Cancer Research (IABCR) Conference
- Egmond aan Zee, The Netherlands, Netherlands
Duration: 15 Apr 201918 Apr 2019
https://www.iabcr.net

Conference

Conference31st International Association for
Breast Cancer Research (IABCR) Conference
Abbreviated titleIABCR 2019
Country/TerritoryNetherlands
Period15/04/201918/04/2019
Internet address

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