IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer
L.S. Ong, Wee Chyan Lee, Shijun Ma, Gokce Oguz, Zhitong Niu, Bao Yi, Mubaraka Yusuf, Puay Leng Lee, Jian Yuan Goh, Panpan Wang, Kylie Su Mei Yong, Qingfeng Chen, Wenyu Wang, Adaikalavan Ramasamy, Dave S.�B. Hoon, Henrik J. Ditzel, Ern Yu Tan, Soo Chin Lee, Qiang Yu
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.