Paclitaxel Induces Micronucleation and Activates Pro-Inflammatory cGAS–STING Signaling in Triple-Negative Breast Cancer

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/m2) 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.

Transcriptomics and Proteomics Characterizing the Anticancer Mechanisms of Natural Rebeccamycin Analog Loonamycin in Breast Cancer Cells

“…Next, the effects of LM on the growth and formation of subcutaneous xenograft nodes derived from the inoculated MDA-MB-468 cells in vivo in BALB/c nude mice were investigated. Both the volumes and weights of the formed MDA-MB-468 cells tumor nodes were reduced by LM administration every 2 days for a total of 17 days at a concentration of 10 mg/kg or 20 mg/kg LM by i.v., compared to 15 mg/kg for paclitaxel as a positive control [ 9 ] by i.p. and 2% DMSO as vehicle by i.v.…”

The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models

“…Our finding that eribulin enhances STING agonist induced IFNβ expression within 3–6 h in a manner distinct from paclitaxel indicates that this acute effect on STING signaling is separate from the antimitotic effects of eribulin. However, it is important to note that other studies have demonstrated that chronic treatment with either stabilizers or destabilizers can activate the cGAS-STING pathway after prolonged mitotic arrest due to chromosome instability and micronucleation that can result from mitotic slippage [ 63 ]. These micronuclei have weak membranes that can release double-stranded DNA into the cytoplasm and activate the cGAS-STING pathway, leading to IFNβ expression when cells are exposed to either microtubule stabilizing or destabilizing MTAs for 24 h or longer [ 63 ].…”

“…However, it is important to note that other studies have demonstrated that chronic treatment with either stabilizers or destabilizers can activate the cGAS-STING pathway after prolonged mitotic arrest due to chromosome instability and micronucleation that can result from mitotic slippage [ 63 ]. These micronuclei have weak membranes that can release double-stranded DNA into the cytoplasm and activate the cGAS-STING pathway, leading to IFNβ expression when cells are exposed to either microtubule stabilizing or destabilizing MTAs for 24 h or longer [ 63 ]. We propose that the acute, interphase effects that are unique to the microtubule destabilizing MTAs would be particularly beneficial in solid tumors that have a low mitotic index [ 64 ] and could enhance STING signaling within the timeframe that they are present in serum at the concentrations where we observe these effects [ 31 ].…”

Emerging role of STING signalling in CNS injury: inflammation, autophagy, necroptosis, ferroptosis and pyroptosis

“…Micronuclei [ 121 ], mtDNA [ 110 ], abnormal cell cycle [ 122 ], and cytoplasmic chromatin fragments [ 123 ] can activate STING in a cGAS-dependent manner. Several stimuli other than cGAMP, which is catalysed by cGAS, such as bacterial or virus cyclic dinucleotides (CDNs) [ 124 , 125 ], can also directly activate STING.…”