SAMHD1 silencing cooperates with radiotherapy to enhance anti-tumor immunity through IFI16-STING pathway in lung adenocarcinoma

Journal of Translational Medicine

Research

Yan Gong¹  Xueping Jiang²  Yangyi Li²  Yajie Cheng²  Jianguo Zhang²  Xinyu Liu²  Yuke Gao²  Liexi Xu²  Zhengrong Huang³  Conghua Xie⁴ 

[1] Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 430071, Wuhan, Hubei, China;Tumor Precision Diagnosis and Treatment Technology and Translational Medicine, Hubei Engineering Research Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, Hubei, China;Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, Hubei, China;Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, Hubei, China;Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 430071, Wuhan, Hubei, China;Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 430071, Wuhan, Hubei, China;Hubei Key Laboratory of Tumor Biological Behaviors, Zhongnan Hospital of Wuhan University, 430071, Wuhan, Hubei, China;Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, Hubei, China;

关键词: SAMHD1;    IFI16;    STING;    Anti-tumor immunity;    Radiotherapy;    Lung adenocarcinoma;   

DOI  :  10.1186/s12967-022-03844-3

 received in 2022-10-11, accepted in 2022-12-22,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundSterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) is a DNA end resection factor, which is involved in DNA damage repair and innate immunity. However, the role of SAMHD1 in anti-tumor immunity is still unknown. This study investigated the effects of SAMHD1 on stimulator of interferon genes (STING)-type I interferon (IFN) pathway and radiation-induced immune responses.MethodsThe roles of SAMHD1 in the activation of cytosolic DNA sensing STING pathway in lung adenocarcinoma (LUAD) cells were investigated with flow cytometry, immunofluorescence, immunoblotting and qPCR. The combined effects of SAMHD1 silencing and radiation on tumor cell growth and STING pathway activation were also evaluated with colony formation and CCK8 assay. The Lewis lung cancer mouse model was used to evaluate the combined efficiency of SAMHD1 silencing and radiotherapy in vivo. Macrophage M1 polarization and cytotoxic T cell infiltration were evaluated with flow cytometry.ResultsThe single-stranded DNA (ssDNA) accumulated in the cytosol of SAMHD1-deficient lung adenocarcinoma (LUAD) cells, accompanied by upregulated DNA sensor IFN-γ-inducible protein 16 (IFI16) and activated STING pathway. The translocation of IFI16 from nucleus to cytosol was detected in SAMHD1-deficient cells. IFI16 and STING were acquired in the activation of STING-IFN-I pathway in SAMHD1-deficient cells. SAMHD1 silencing in LUAD cells promoted macrophage M1 polarization in vitro. SAMHD1 silencing synergized with radiation to activate ssDNA-STING-IFN-I pathway, inhibit proliferation, promote apoptosis and regulate cell cycle. SAMHD1 silencing cooperated with radiotherapy to inhibit tumor growth and increase CD86+MHC-IIhigh M1 proportion and CD8+ T cell infiltration in vivo.ConclusionsSAMHD1 deficiency induced IFN-I production through cytosolic IFI16-STING pathway in LUAD cells. Moreover, SAMHD1 downregulation and radiation cooperated to inhibit tumor growth and enhance anti-tumor immune responses through macrophage M1 polarization and CD8+ T cell infiltration. Combination of SAMHD1 inhibition and radiotherapy may be a potentially therapeutic strategy for LUAD patients.

【 授权许可】

CC BY   
© The Author(s) 2022

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