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.
- 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.
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.