癌症研究
生物
细胞毒性T细胞
乳腺癌
CD8型
癌症
癌细胞
免疫学
免疫系统
体外
遗传学
生物化学
作者
Yong Wang,Weibo Luo,Yan Chen,Yijie Wang,Bo Zhang,Zhenhua Ren,Lei Bao,Yanan Wang,Jennifer E. Wang,Yang–Xin Fu
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2021-01-01
卷期号:81 (1): 174-186
被引量:11
标识
DOI:10.1158/0008-5472.can-20-1710
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI