1. Academic Validation
  2. 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.
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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