ZMYND8 Expression in Breast Cancer Cells Blocks T-Lymphocyte Surveillance to Promote Tumor Growth.

Abstract

Emerging studies indicate that DNA damage in cancer cells triggers antitumor immunity, but its intrinsic regulatory mechanism in breast cancer cells remains poorly understood. Here, we show that ZMYND8 is upregulated and inhibits micronucleus formation and DNA damage in breast cancer cells. Loss of ZMYND8 triggered activation of the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase in micronuclei, leading to further activation of the downstream signaling effectors stimulator of IFN genes and NF-κB, but not TANK-binding kinase 1 and IFN regulatory factor 3, thereby inducing the expression of IFNβ and IFN-stimulated genes (ISG) in breast cancer cells in vitro and tumors in vivo. ZMYND8 knockout (KO) in breast cancer cells promoted infiltration of CD4+ and CD8+ T cells, leading to tumor inhibition in syngeneic mouse models, which was significantly attenuated by treatment of anti-CD4/CD8-depleting antibodies or anti-IFNAR1 antibody and in immunodeficient Rag1 KO mice. In human breast tumors, ZMYND8 was negatively correlated with ISGs, CD4, CD8A, CD8B, and the tumor-lymphocyte infiltration phenotype. Collectively, these findings demonstrate that maintenance of genome stability by ZMYND8 causes breast cancer cells to evade cytotoxic T-lymphocyte surveillance, which leads to tumor growth. SIGNIFICANCE: These findings show that ZMYND8 is a new negative and intrinsic regulator of the innate immune response in breast tumor cells, and ZMYND8 may be a possible target for antitumor immunotherapy.

• Authors: Yong Wang, Maowu Luo, Yan Chen, Yijie Wang, Bo Zhang, Zhenhua Ren, Lei Bao, Yanan Wang, Jennifer E Wang, Yang-Xin Fu, Weibo Luo, Yingfei Wang
• Journal: Cancer research (Cancer Res) Vol. 81 Issue 1 Pg. 174-186 (01 01 2021) ISSN: 1538-7445 [Electronic] United States
• PMID: 33148660 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• Biomarkers, Tumor
• Homeodomain Proteins
• Tumor Suppressor Proteins
• ZMYND8 protein, human
• RAG-1 protein

Topics

• Animals
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Breast Neoplasms (immunology, metabolism, pathology)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Movement
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Homeodomain Proteins (physiology)
• Humans
• Lymphocytes, Tumor-Infiltrating (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• T-Lymphocytes, Cytotoxic (immunology)
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (genetics, metabolism)
• Xenograft Model Antitumor Assays