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 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

doi:10.1158/2326-6066.CIR-21-0826

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 Malladi, Siamak Tabrizi, Sangeetha M. Reddy, Seoyun Yum, Ching Wei Chang, Katherine E. Hutchinson, Susan E. YostYuan Yuan, Zhijian J. Chen, Yang-Xin Fu, Ariella B. Hanker, Carlos L. Arteaga

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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 MYCoverexpressing TNBC.

Original language	English (US)
Pages (from-to)	829-843
Number of pages	15
Journal	Cancer Immunology Research
Volume	10
Issue number	7
DOIs	https://doi.org/10.1158/2326-6066.CIR-21-0826
State	Published - Jul 2022

ASJC Scopus subject areas

General Medicine

Access to Document

10.1158/2326-6066.CIR-21-0826

Cite this

Lee, K. M., Lin, C. C., Servetto, A., Bae, J., Kandagatla, V., Ye, D., Kim, G. M., Sudhan, D. R., Mendiratta, S., Ericsson, P. I. G., Balko, J. M., Lee, J., Barnes, S., Malladi, V., Tabrizi, S., Reddy, S. M., Yum, S., Chang, C. W., Hutchinson, K. E., ... Arteaga, C. L. (2022). Epigenetic Repression of STING by MYC Promotes Immune Evasion and Resistance to Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer. Cancer Immunology Research, 10(7), 829-843. https://doi.org/10.1158/2326-6066.CIR-21-0826

Lee, KM, Lin, CC, Servetto, A, Bae, J, Kandagatla, V, Ye, D, Kim, GM, Sudhan, DR, Mendiratta, S, Ericsson, PIG, Balko, JM, Lee, J, Barnes, S, Malladi, V, Tabrizi, S, Reddy, SM, Yum, S, Chang, CW, Hutchinson, KE, Yost, SE, Yuan, Y, Chen, ZJ, Fu, Y-X, Hanker, AB & Arteaga, CL 2022, 'Epigenetic Repression of STING by MYC Promotes Immune Evasion and Resistance to Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer', Cancer Immunology Research, vol. 10, no. 7, pp. 829-843. https://doi.org/10.1158/2326-6066.CIR-21-0826

@article{07b27b1edd4e4e329b574dd882e7e625,

title = "Epigenetic Repression of STING by MYC Promotes Immune Evasion and Resistance to Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer",

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 MYCoverexpressing TNBC.",

author = "Lee, {Kyung Min} and Lin, {Chang Ching} and Alberto Servetto and Joonbeom Bae and Vishal Kandagatla and Dan Ye and Kim, {Gun Min} and Sudhan, {Dhivya R} and Saurabh Mendiratta and Ericsson, {Paula I.Gonz{\'a}lez} and Balko, {Justin M.} and Jeon Lee and Spencer Barnes and Venkat Malladi and Siamak Tabrizi and Reddy, {Sangeetha M.} and Seoyun Yum and Chang, {Ching Wei} and Hutchinson, {Katherine E.} and Yost, {Susan E.} and Yuan Yuan and Chen, {Zhijian J.} and Yang-Xin Fu and Hanker, {Ariella B.} and Arteaga, {Carlos L.}",

note = "Publisher Copyright: {\textcopyright} 2022 American Association for Cancer Research.",

year = "2022",

month = jul,

doi = "10.1158/2326-6066.CIR-21-0826",

language = "English (US)",

volume = "10",

pages = "829--843",

journal = "Cancer Immunology Research",

issn = "2326-6066",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

TY - JOUR

T1 - Epigenetic Repression of STING by MYC Promotes Immune Evasion and Resistance to Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer

AU - Lee, Kyung Min

AU - Lin, Chang Ching

AU - Servetto, Alberto

AU - Bae, Joonbeom

AU - Kandagatla, Vishal

AU - Ye, Dan

AU - Kim, Gun Min

AU - Sudhan, Dhivya R

AU - Mendiratta, Saurabh

AU - Ericsson, Paula I.González

AU - Balko, Justin M.

AU - Lee, Jeon

AU - Barnes, Spencer

AU - Malladi, Venkat

AU - Tabrizi, Siamak

AU - Reddy, Sangeetha M.

AU - Yum, Seoyun

AU - Chang, Ching Wei

AU - Hutchinson, Katherine E.

AU - Yost, Susan E.

AU - Yuan, Yuan

AU - Chen, Zhijian J.

AU - Fu, Yang-Xin

AU - Hanker, Ariella B.

AU - Arteaga, Carlos L.

PY - 2022/7

Y1 - 2022/7

N2 - 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 MYCoverexpressing TNBC.

AB - 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 MYCoverexpressing TNBC.

UR - http://www.scopus.com/inward/record.url?scp=85133980923&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85133980923&partnerID=8YFLogxK

U2 - 10.1158/2326-6066.CIR-21-0826

DO - 10.1158/2326-6066.CIR-21-0826

M3 - Article

C2 - 35561311

AN - SCOPUS:85133980923

SN - 2326-6066

VL - 10

SP - 829

EP - 843

JO - Cancer Immunology Research

JF - Cancer Immunology Research

IS - 7

ER -

Epigenetic Repression of STING by MYC Promotes Immune Evasion and Resistance to Immune Checkpoint Inhibitors in Triple-Negative Breast Cancer

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this