SAMHD1 Silencing Cooperates with Radiotherapy to Enhance Anti-tumor Immunity Through IFI16-STING Pathway in Lung Adenocarcinoma

Overview

Journal J Transl Med

Publisher Biomed Central

Specialties Biomedical Engineering
General Medicine

Date 2022 Dec 28

PMID 36578072

Authors

Yangyi Li

Yuke Gao

Xueping Jiang

Yajie Cheng

Jianguo Zhang

Liexi Xu

Xinyu Liu

Zhengrong Huang

Conghua Xie

Yan Gong

Affiliations

Soon will be listed here.

Abstract

Background: Sterile 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.

Methods: The 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.

Results: The 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 CD86MHC-II M1 proportion and CD8 T cell infiltration in vivo.

Conclusions: SAMHD1 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.

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References

McLaughlin M, Patin E, Pedersen M, Wilkins A, Dillon M, Melcher A . Inflammatory microenvironment remodelling by tumour cells after radiotherapy. Nat Rev Cancer. 2020; 20(4):203-217. DOI: 10.1038/s41568-020-0246-1. View

Wang Y, Zhao W, Bai S, Feng L, Bie S, Gong L . MRNIP condensates promote DNA double-strand break sensing and end resection. Nat Commun. 2022; 13(1):2638. PMC: 9098523. DOI: 10.1038/s41467-022-30303-w. View

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

Mosser D, Edwards J . Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008; 8(12):958-69. PMC: 2724991. DOI: 10.1038/nri2448. View

Herold N, Rudd S, Ljungblad L, Sanjiv K, Hed Myrberg I, Paulin C . Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies. Nat Med. 2017; 23(2):256-263. DOI: 10.1038/nm.4265. View

Vanpouille-Box C, Alard A, Aryankalayil M, Sarfraz Y, Diamond J, Schneider R . DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun. 2017; 8:15618. PMC: 5472757. DOI: 10.1038/ncomms15618. View

Li Z, Huan C, Wang H, Liu Y, Liu X, Su X . TRIM21-mediated proteasomal degradation of SAMHD1 regulates its antiviral activity. EMBO Rep. 2019; 21(1):e47528. PMC: 6944907. DOI: 10.15252/embr.201847528. View

Conway E, Pikor L, Kung S, Hamilton M, Lam S, Lam W . Macrophages, Inflammation, and Lung Cancer. Am J Respir Crit Care Med. 2015; 193(2):116-30. DOI: 10.1164/rccm.201508-1545CI. View

Yang C, Huang H, Chang Y, Lin C, Lai I, Chang J . DNA-Sensing and Nuclease Gene Expressions as Markers for Colorectal Cancer Progression. Oncology. 2016; 92(2):115-124. DOI: 10.1159/000452281. View

10.

Chen S, Bonifati S, Qin Z, St Gelais C, Kodigepalli K, Barrett B . SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways. Proc Natl Acad Sci U S A. 2018; 115(16):E3798-E3807. PMC: 5910870. DOI: 10.1073/pnas.1801213115. View

11.

Maelfait J, Bridgeman A, Benlahrech A, Cursi C, Rehwinkel J . Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1. Cell Rep. 2016; 16(6):1492-1501. PMC: 4978700. DOI: 10.1016/j.celrep.2016.07.002. View

12.

Weinreb J, Ghazale N, Pradhan K, Gupta V, Potts K, Tricomi B . Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production. Dev Cell. 2021; 56(5):627-640.e5. PMC: 8258699. DOI: 10.1016/j.devcel.2021.02.006. View

13.

Rizvi N, Hellmann M, Snyder A, Kvistborg P, Makarov V, Havel J . Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015; 348(6230):124-8. PMC: 4993154. DOI: 10.1126/science.aaa1348. View

14.

Unterholzner L, Keating S, Baran M, Horan K, Jensen S, Sharma S . IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol. 2010; 11(11):997-1004. PMC: 3142795. DOI: 10.1038/ni.1932. View

15.

Emam A, Wu X, Xu S, Wang L, Liu S, Wang B . Stalled replication fork protection limits cGAS-STING and P-body-dependent innate immune signalling. Nat Cell Biol. 2022; 24(7):1154-1164. PMC: 9924303. DOI: 10.1038/s41556-022-00950-8. View

16.

Almine J, OHare C, Dunphy G, Haga I, Naik R, Atrih A . IFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes. Nat Commun. 2017; 8:14392. PMC: 5316833. DOI: 10.1038/ncomms14392. View

17.

Bhattacharya S, Srinivasan K, Abdisalaam S, Su F, Raj P, Dozmorov I . RAD51 interconnects between DNA replication, DNA repair and immunity. Nucleic Acids Res. 2017; 45(8):4590-4605. PMC: 5416901. DOI: 10.1093/nar/gkx126. View

18.

Ju M, Lee J, Choi Y, Park S, Sul H, Chung H . PWWP2B promotes DNA end resection and homologous recombination. EMBO Rep. 2022; 23(7):e53492. PMC: 9253748. DOI: 10.15252/embr.202153492. View

19.

Pan Y, Yu Y, Wang X, Zhang T . Tumor-Associated Macrophages in Tumor Immunity. Front Immunol. 2020; 11:583084. PMC: 7751482. DOI: 10.3389/fimmu.2020.583084. View

20.

Jonsson K, Laustsen A, Krapp C, Skipper K, Thavachelvam K, Hotter D . IFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP. Nat Commun. 2017; 8:14391. PMC: 5309897. DOI: 10.1038/ncomms14391. View