2. Academic Validation
  3. IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer

IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer

  • Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2201376119. doi: 10.1073/pnas.2201376119.
Li-Teng Ong 1,  Wee Chyan Lee 1,  Shijun Ma 1,  Gokce Oguz 1,  Zhitong Niu 2,  Yi Bao 1,  Mubaraka Yusuf 1,  Puay Leng Lee 1,  Jian Yuan Goh 1,  Panpan Wang 3,  Kylie Su Mei Yong 4,  Qingfeng Chen 4,  Wenyu Wang 2,  Adaikalavan Ramasamy 1,  Dave S B Hoon 5,  Henrik J Ditzel 6 7,  Ern Yu Tan 8,  Soo Chin Lee 9 10,  Qiang Yu 1 11 12
Affiliations

Affiliations

  • 1 Agency for Science, Technology, and Research (A*STAR), Genome Institute of Singapore, 138672 Singapore.
  • 2 The Sixth Affiliated Hospital, Sun Yat-sen University, 510275 Guangzhou, China.
  • 3 The First Affiliated Hospital, Jinan University, 510632 Guangzhou, China.
  • 4 Agency for Science, Technology and Research (A*STAR), Institute of Molecular and Cell Biology, 138673 Singapore.
  • 5 Department of Translational Molecular Medicine, Saint John's Cancer Institute, Providence Health System, Santa Monica, CA 90404.
  • 6 Department of Oncology, Odense University Hospital, 5000 Odense, Denmark.
  • 7 Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark.
  • 8 Department of General Surgery, Tan Tock Seng Hospital, 308433 Singapore.
  • 9 Cancer Science Institute of Singapore, Yong Loo Lin School of Medicine, National University of Singapore, 119077 Singapore.
  • 10 Department of Haematology-Oncology, National University Cancer Institute, National University Health System, 119228 Singapore.
  • 11 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 119077 Singapore.
  • 12 Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, 169857 Singapore.
PMID: 35878022 DOI: 10.1073/pnas.2201376119
Abstract

Relapse to anti-HER2 monoclonal antibody (mAb) therapies, such as trastuzumab in HER2+ breast Cancer (BC), is associated with residual disease progression due to resistance to therapy. Here, we identify interferon-γ inducible protein 16 (IFI16)-dependent STING signaling as a significant determinant of trastuzumab responses in HER2+ BC. We show that down-regulation of immune-regulated genes (IRG) is specifically associated with poor survival of HER2+, but not Other BC subtypes. Among IRG, IFI16 is identified as a direct target of EZH2, the underexpression of which leads to deficient STING activation and downstream CXCL10/11 expression in response to trastuzumab treatment. Dual inhibition of EZH2 and histone deacetylase (HDAC) significantly activates IFI16-dependent immune responses to trastuzumab. Notably, a combination of a novel histone methylation inhibitor with an HDAC Inhibitor induces complete tumor eradication and long-term T cell memory in a HER2+ BC mouse model. Our findings demonstrate an epigenetic regulatory mechanism suppressing the expression of the IFI16-CXCL10/11 signaling pathway that provides a survival advantage to HER2+ BC to confer resistance to trastuzumab treatment.

Keywords

HER2+ breast cancer; HER2-targeted therapy; anti-HER2 resistance; epigenetic approach.

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