| المساهمون: |
Lee, Kyung-Min, Lin, Chang-Ching, Servetto, Alberto, Bae, Joonbeom, Kandagatla, Vishal, Ye, Dan, Kim, Gunmin, Sudhan, Dhivya R, Mendiratta, Saurabh, González Ericsson, Paula I, Balko, Justin M, Lee, Jeon, Barnes, Spencer, Malladi, Venkat S, Tabrizi, Siamak, Reddy, Sangeetha M, Yum, Seoyun, Chang, Ching-Wei, Hutchinson, Katherine E, Yost, Susan E, Yuan, Yuan, Chen, Zhijian J, Fu, Yang-Xin, Hanker, Ariella B, Arteaga, Carlos L |
| الوصف: |
The MYC oncogene is frequently amplified in triple-negative breast cancer (TNBC). Here, we show that MYC suppression induces immune-related hallmark gene set expression and tumor-infiltrating T cells in MYC-hyperactivated TNBCs. Mechanistically, MYC repressed stimulator of interferon genes (STING) expression via direct binding to the STING1 enhancer region, resulting in downregulation of the T-cell chemokines CCL5, CXCL10, and CXCL11. In primary and metastatic TNBC cohorts, tumors with high MYC expression or activity exhibited low STING expression. Using a CRISPR-mediated enhancer perturbation approach, we demonstrated that MYC-driven immune evasion is mediated by STING repression. STING repression induced resistance to PD-L1 blockade in mouse models of TNBC. Finally, a small-molecule inhibitor of MYC combined with PD-L1 blockade elicited a durable response in immune-cold TNBC with high MYC expression, suggesting a strategy to restore PD-L1 inhibitor sensitivity in MYC-overexpressing TNBC. |