Journal article
Paclitaxel Induces Micronucleation and Activates Pro-Inflammatory cGAS-STING Signaling in Triple-Negative Breast Cancer
Molecular cancer therapeutics, Vol.20(12), pp.2553-2567
12/01/2021
DOI: 10.1158/1535-7163.MCT-21-0195
PMCID: PMC8643310
PMID: 34583980
Abstract
Taxanes remain one of the most effective medical treatments for breast cancer. Clinical trials have coupled taxanes with immune checkpoint inhibitors in patients with triple-negative breast cancer (TNBC) with promising results. However, the mechanism linking taxanes to immune activation is unclear. To determine if paclitaxel could elicit an antitumoral immune response, we sampled tumor tissues from patients with TNBC receiving weekly paclitaxel (80 mg/m
) and found increased stromal tumor-infiltrating lymphocytes and micronucleation over baseline in three of six samples. At clinically relevant concentrations, paclitaxel can induce chromosome missegregation on multipolar spindles during mitosis. Consequently, post-mitotic cells are multinucleated and contain micronuclei, which often activate cyclic GMP-AMP synthase (cGAS) and may induce a type I IFN response reliant on the stimulator of IFN genes (STING) pathway. Other microtubule-targeting agents, eribulin and vinorelbine, recapitulate this cGAS/STING response and increased the expression of immune checkpoint molecule, PD-L1, in TNBC cell lines. To test the possibility that microtubule-targeting agents sensitize tumors that express cGAS to immune checkpoint inhibitors, we identified 10 patients with TNBC treated with PD-L1 or PD-1, seven of whom also received microtubule-targeting agents. Elevated baseline cGAS expression significantly correlated with treatment response in patients receiving microtubule-targeting agents in combination with immune checkpoint inhibitors. Our study identifies a mechanism by which microtubule-targeting agents can potentiate an immune response in TNBC. Further, baseline cGAS expression may predict patient treatment response to therapies combining microtubule-targeting agents and immune checkpoint inhibitors.
Details
- Title: Subtitle
- Paclitaxel Induces Micronucleation and Activates Pro-Inflammatory cGAS-STING Signaling in Triple-Negative Breast Cancer
- Creators
- Yang Hu - University of Wisconsin–MadisonBaraa K Manasrah - University of Wisconsin–MadisonStephanie M McGregor - University of Wisconsin–MadisonRobert F Lera - University of Wisconsin–MadisonRoshan X Norman - University of Wisconsin–MadisonJohn B Tucker - University of Wisconsin–MadisonChristina M Scribano - University of Wisconsin–MadisonRachel E Yan - University of Wisconsin–MadisonMouhita Humayun - University of Wisconsin–MadisonKari B Wisinski - University of Wisconsin–MadisonAmye J Tevaarwerk - University of Wisconsin–MadisonRuth M O'Regan - University of Wisconsin–MadisonLee G Wilke - University of Wisconsin–MadisonBeth A Weaver - University of Wisconsin–MadisonDavid J Beebe - University of Wisconsin–MadisonNing Jin - University of Wisconsin–MadisonMark E Burkard - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics, Vol.20(12), pp.2553-2567
- DOI
- 10.1158/1535-7163.MCT-21-0195
- PMID
- 34583980
- PMCID
- PMC8643310
- NLM abbreviation
- Mol Cancer Ther
- ISSN
- 1535-7163
- eISSN
- 1538-8514
- Grant note
- T32 CA009135 / NCI NIH HHS T32 HL007899 / NHLBI NIH HHS P30 CA014520 / NCI NIH HHS T32 GM140935 / NIGMS NIH HHS F31 CA247248 / NCI NIH HHS T32 GM008692 / NIGMS NIH HHS R01 AI134749 / NIAID NIH HHS R01 CA186134 / NCI NIH HHS R01 CA234904 / NCI NIH HHS
- Language
- English
- Date published
- 12/01/2021
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984701255702771
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