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

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-induced IFN-I activation was not affected by Batf2 deletion. BATF2 interacted with STING, promoting its phosphorylation and oligomerization. Glutamine is enriched in the TME. We found that glutamine inhibited the BATF2-STING pathway by increasing a repressive epigenetic marker, H3K27me3, on the promoters of BATF2 and IFNB1. The expression of BATF2 in cancer cells resulted in IFN-I- and γδ T-cell-dependent tumor rejection. Single-cell immune profiling showed that Batf2-expressing tumors contained significantly expanded Cxcl10+ myeloid cells and γδ T-cells. Utilizing the 4-NQO-induced HNSCC model, we found that BATF2 limited suppressive myeloid cells and expanded effector cells in the TME, serving as a potent tumor suppressor. Conclusion: BATF2 is a glutamine-responsive tumor suppressor that limits tumor initiation by engaging the STING-γδ T-cell pathway. Acknowledgments: This work was supported by NIH grants R01 DE026728, U01 DE029255, R01 DE031951, and U01 DE033330 Citation Format: Wang Gong, Hülya Taner, Yuesong Wu, Zaiye Li, Wanqing Cheng, Christopher Donnelly, Felipe Nör, Yumin He, Zackary Fitzsimonds, Jianqian Li, Haitao Wen, Steven Chinn, Yuying Xie, James Moon, Yu Leo Lei. Metabolic inhibition of BATF2 dampens type-I interferon-mediated immune sensing of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3927.