| Title: |
Epigenetic Repression of STING by MYC Promotes Immune Evasion and Resistance to Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer |
| Authors: |
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 |
| Contributors: |
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 |
| Publication Year: |
2022 |
| Collection: |
IRIS Università degli Studi di Napoli Federico II |
| Subject Terms: |
Animal; B7-H1 Antigen; Cell Line; Tumor; Epigenetic Repression; Human; Immune Checkpoint Inhibitor; Immune Evasion; Membrane Protein; Mice; Proto-Oncogene Proteins c-myc; Triple Negative Breast Neoplasms |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/wos/WOS:000824214800001; volume:10; issue:7; firstpage:829; lastpage:843; numberofpages:15; journal:CANCER IMMUNOLOGY RESEARCH; https://hdl.handle.net/11588/901716 |
| DOI: |
10.1158/2326-6066.CIR-21-0826 |
| Availability: |
https://hdl.handle.net/11588/901716; https://doi.org/10.1158/2326-6066.CIR-21-0826 |
| Rights: |
info:eu-repo/semantics/openAccess ; license:Dominio pubblico ; license uri:http://creativecommons.org/publicdomain/zero/1.0/ |
| Accession Number: |
edsbas.620CDACC |
| Database: |
BASE |