Work

Augmenting Type 1 interferon antitumoral immune signaling in triple-negative breast cancer (TNBC) via combined radiotherapy and monopolar spindle kinase I (Mps1) inhibition 3799

Year: 2025

Type: article

Abstract: Description Triple-negative breast cancer (TNBC) exhibits inferior durable response to radiation treatment (RT) and worse locoregional and distant control, leading to poor clinical outcomes. Thus, there is an urgent need for effective novel TNBC therapies. Monopolar spindle kinase I (Mps1) regulates cell division and is upregulated in TNBC. Type 1 interferon (T1IFN) activates cytotoxic immune cells and improves tumor control. RT potentiates T1IFN signaling, but it is unknown whether this can be enhanced with combined Mps1 inhibition. Our objective was to examine the effect of Mps1 inhibition and RT on T1IFN production in TNBC. Mps1 inhibition (via empesertib or CFI-402257) combined with RT inhibited TNBC growth in vitro and in vivo. TTK inhibition and RT increased micronuclei in syngeneic and human TNBC cells (p < 0.0001) as detected via micronuclei formation assays. TTK inhibition and RT induced T1IFN signaling in the T1IFNβ-GFP TNBC reporter system (p < 0.0001). Combination also promoted expression of the T1IFN genes Cxcl10 and Ccl5 in human and syngeneic TNBC cells and upregulated MHC1 and PD-L1 as measured via RT-qPCR and flow cytometry. These data demonstrate that Mps1 inhibition radiosensitizes TNBC models through increased micronuclei formation and induces T1IFN signaling, suggesting that combination therapy might more effectively treat TNBC and potentiate immune responses in women with TNBC. Future work will examine the underlying implications on the antitumoral immune response. Funding Sources Breast Cancer Research Foundation (BCRF), PSTP Training Grant (T32-GM007767), Rackham Graduate School Predoctoral Fellowship Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1559