Topoisomerase II inhibitors induce cGAS-STING dependent inflammation resulting in cytokine induction and immune checkpoint activation release_kj3s4xy4rzfg3doe33ji27fuke

by Richard D.A. Wilkinson, Nuala McCabe, Eileen E Parkes, Eliana M Barros, David I Johnston, Rayhaan Ali, Katrina Lappin, Roger Greenberg, D. Paul Harkin, Stuart A McIntosh, Richard D Kennedy, Kienan I Savage

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Tumours with genomic instability demonstrate enhanced immunogenicity and potential for response to immune checkpoint blockade (ICB). We previously demonstrated activation of the cGAS-STING pathway following loss of DNA repair, resulting in cytokine induction, lymphocytic infiltration and immune checkpoint activation. Here we explore the role of chemotherapies in inducing this innate immune response, identifying topoisomerase II (topo-II) inhibitors, particularly doxorubicin, as potent inducers of a cGAS-STING dependent interferon response. Mechanistically, topo-II inhibition resulted in significant induction of cytoplasmic DNA and subsequent micronuclei formation, a requirement for efficient cGAS-STING activation, and consequent cytokine and immune checkpoint gene induction. Importantly, increased cytokine and immune checkpoint gene expression, as well as increased immune cell infiltration, was also observed in patient derived breast tumour biopsies following topo-II inhibitor-based treatment. Taken together, this study indicates topo-II inhibitors such as doxorubicin, may be best placed to induce immunogenic inflammation, and thereby increase responses to ICB therapies.
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Date   2019-09-10
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