Cell-autonomous Inflammation of BRCA1-deficient Ovarian Cancers Drives Intrinsic Immunoreactivity and Immune Resistance through STING and VEGF
收藏干细胞与再生医学数据中心2022-02-20 更新2024-03-06 收录
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资源简介：
BRCA1 loss leads to tumor cell transcriptional reprogramming, resulting in a DNA damage-driven, mandatory cell-autonomous type I IFN inflammatory activation mediated by STING and TREX1/2. PARP inhibition augmented this immunoreactivity, creating contextual lethality to dual immune checkpoint blockade (ICB) in vivo. BRCA1-deficient tumor can escape T-cell inflammation through targeted deletion or methylation of the DNA sensing/IFN pathway genes, such as STING, IFNB1 or the chemokine CCL5. Alternatively, BRCA-mutated carcinomas retaining immunoreactivity upregulate their VEGF-A expression driven by STING, which mediates immune resistance and tumor progression. STING elimination attenuated tumor growth and abrogated therapeutic resistance to dual ICB. VEGF-A blockade synergized with immune checkpoint blockade and/or PARP inhibition to control outgrowth of Brca1-/- ovarian tumors, offering opportunities for rational combination therapy of cancers with homologous recombination repair deficiency (HRD).
提供机构：
Centre hospitalier universitaire vaudois
创建时间：
2022-02-20
