Abstract 3927: Metabolic inhibition of BATF2 dampens type-I interferon-mediated immune sensing of cancer

作者：Wang Gong, Hülya F. Taner, Yuesong Wu, Zaiye Li, Wanqing Cheng, Christopher R. Donnelly, Felipe Nör, HE Yu-min, Zackary R. Fitzsimonds, Jianqian Li, Haitao Wen, Steven B. Chinn, Yuying Xie, James J. Moon, Yu L. Lei · 发表于：Cancer Research · 年份：2024 · DOI：10.1158/1538-7445.am2024-3927 · 研究领域：Cancer, Hypoxia, and Metabolism

Abstract Background: The type-I interferon (IFN-I) system appeared before adaptive immunity during evolution as the primary defense system for metazoans. Initiating cancers frequently disable this first line of defense before establishing T-cell exhaustion programs. However, the molecules linking IFN-I, danger signals, and unique metabolic conditions in the tumor microenvironment (TME) remain to be discovered. Methods: We performed centered log-ratio transformation on the cluster composition data using the R-package ALDEx2 to compare the clusters in single-cell data sets. IFN-I signatures were quantified using qPCR and ELISA. ChIP was performed to examine the H3K27me3 epigenetic marker on the promoters of BATF2 and IFN-I genes in bone marrow-derived macrophage (BMDM). For the cigarette smoke carcinogen-induced head and neck squamous cell carcinoma (HNSCC) model, experimental mice were fed with water containing 50 μg/mL of 4-NQO for 16 weeks and then switched to regular feeding water. We started monitoring 10 weeks post-treatment for the number, location, and diameter of the lesions. TME analysis was performed using single-cell RNA-Seq and multispectral imaging. Results: We analyzed three large independent cohorts of patients and found that BATF2 strongly correlated with the immunogenicity of HNSCC, with a stronger correlation coefficient than STING. We generated Batf2−/− BMDM and found that Batf2 deficiency rendered cells insensitive to STING agonists. However, the dsRNA-indu...