IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer.
Proceedings of the National Academy of Sciences of the United States of America
california; sjci; Animals; Antineoplastic Agents, Immunological; Breast Neoplasms; Cell Line, Tumor; Chemokine CXCL10; Chemokine CXCL11; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Immunity; Membrane Proteins; Mice; Neoplasm Recurrence, Local; Nuclear Proteins; Phosphoproteins; Receptor, ErbB-2; Signal Transduction; Trastuzumab
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.
Women & Children
Ong, Li-Teng; Lee, Wee Chyan; Ma, Shijun; Oguz, Gokce; Niu, Zhitong; Bao, Yi; Yusuf, Mubaraka; Lee, Puay Leng; Goh, Jian Yuan; Wang, Panpan; Yong, Kylie Su Mei; Chen, Qingfeng; Wang, Wenyu; Ramasamy, Adaikalavan; Hoon, Dave; Ditzel, Henrik J; Tan, Ern Yu; Lee, Soo Chin; and Yu, Qiang, "IFI16-dependent STING signaling is a crucial regulator of anti-HER2 immune response in HER2+ breast cancer." (2022). Articles, Abstracts, and Reports. 6410.