TY - JOUR
T1 - ZMYND8 Expression in Breast Cancer Cells Blocks T-Lymphocyte Surveillance to Promote Tumor Growth
AU - Wang, Yong
AU - Luo, Maowu
AU - Chen, Yan
AU - Wang, Yijie
AU - Zhang, Bo
AU - Ren, Zhenhua
AU - Bao, Lei
AU - Wang, Yanan
AU - Wang, Jennifer E.
AU - Fu, Yang Xin
AU - Luo, Weibo
AU - Wang, Yingfei
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - 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-kB, but not TANK-binding kinase 1 and IFN regulatory factor 3, thereby inducing the expression of IFNb 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 CD4þ and CD8þ T cells, leading to tumor inhibition in syngeneic mouse models, which was significantly attenuated by treatment of anti-CD4/CD8–depleting antibodies or antiIFNAR1 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.
AB - 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-kB, but not TANK-binding kinase 1 and IFN regulatory factor 3, thereby inducing the expression of IFNb 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 CD4þ and CD8þ T cells, leading to tumor inhibition in syngeneic mouse models, which was significantly attenuated by treatment of anti-CD4/CD8–depleting antibodies or antiIFNAR1 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.
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U2 - 10.1158/0008-5472.CAN-20-1710
DO - 10.1158/0008-5472.CAN-20-1710
M3 - Article
C2 - 33148660
AN - SCOPUS:85100436580
SN - 0008-5472
VL - 81
SP - 174
EP - 186
JO - Cancer research
JF - Cancer research
IS - 1
ER -