Epigenetic Repression of STING by MYC Promotes Immune Evasion and Resistance to Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer
Kyung‐min Lee, Chang‐Ching Lin, Alberto Servetto, Joonbeom Bae, Vishal Kandagatla, Dan Ye, Gun Min Kim, Dhivya R. Sudhan, Saurabh Mendiratta, Paula I. González-Ericsson, Justin M. Balko, Jeon Lee, Spencer Barnes, Venkat S. Malladi, Siamak Tabrizi, Sangeetha M. Reddy, Seoyun Yum, Ching‐Wei Chang, Katherine E. Hutchinson, Susan E. Yost, Yuan Yuan, Zhijian J. Chen, Yang‐Xin Fu, Ariella B. Hanker, Carlos L. Arteaga
Abstract
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.