Targeting CCR2+ macrophages with BET inhibitor overcomes adaptive resistance to anti-VEGF therapy in ovarian cancer

Autor: Yutuan Wu, Nicholas B. Jennings, Yunjie Sun, Santosh K. Dasari, Emine Bayraktar, Sara Corvigno, Elaine Stur, Deanna Glassman, Lingegowda S. Mangala, Adrian Lankenau Ahumada, Shannon N. Westin, Anil K. Sood, Wei Hu
Rok vydání: 2022
Předmět:
Zdroj: Journal of Cancer Research and Clinical Oncology. 148:803-821
ISSN: 1432-1335
0171-5216
DOI: 10.1007/s00432-021-03885-z
Popis: Purpose Tumor-associated macrophages (TAMs) are known to contribute to adaptive resistance to anti-vascular endothelial growth factor (VEGF) antibody (AVA) therapy in ovarian cancer. BET (bromodomain and extra-terminal domain) inhibitors (BETi) may have unique roles in targeting TAMs. Our objective was to examine the effects of BETi on TAMs, especially in the context of enhancing the efficacy of AVA therapy. Methods We conducted a series of in vitro (MTT assay, apoptosis, flow cytometry, and RNA sequencing) and in vivo (xenograft ovarian cancer model) experiments to determine the biological effects of BETi combined with AVA in ovarian cancer. For statistical analysis, a two-tailed Student’s t test (equal variance) or ANOVA was used for multiple groups’ comparison, and p Results BETi resulted in a dose-dependent decrease in cell viability and induced apoptosis (p p p +/CD80+) was significantly increased after treatment with low-dose BETi (ABBV-075 0.1 µM; p +/CCR2+ macrophages was significantly decreased (p + macrophages and re-polarize the macrophages into an M1-like phenotype. RNA-seq analysis revealed that BETi selectively targeted macrophage infiltration-related cytokines/chemokines in ovarian cancer (adjusted p p p Conclusions Our findings indicate a previously unrecognized role for BETi in selectively targeting CCR2+ TAMs and enhancing the efficacy of AVA therapy in ovarian cancer.
Databáze: OpenAIRE
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