Top

Published in:

01-06-2019 | Hepatocellular Carcinoma | Original Article

Sirtuin2 enhances the tumoricidal function of liver natural killer cells in a mouse hepatocellular carcinoma model

Authors: Ming Chen, Min Xu, Chengliang Zhu, Hongling Wang, Qiu Zhao, Feng Zhou

Published in: Cancer Immunology, Immunotherapy | Issue 6/2019

Abstract

Hepatocellular carcinoma (HCC) is the third most lethal cancer in the world. Natural killer (NK) cell-mediated immunity is crucial for tumor surveillance and therapy. Characterization of the regulatory mechanisms of NK cell function is important for developing novel immunotherapies against HCC. In this study, we used a chemical-induced mouse HCC model to identify the upregulation of Sirtuin2 (SIRT2) in liver NK cells. In particular, SIRT2 was predominantly expressed in liver CD94⁺ NK cells. The HCC liver microenvironment induced SIRT2 expression in NK cells. In addition, overexpression of exogenous SIRT2 significantly upregulated the production of cytokines and cytotoxic mediators in activated NK cells. Consistently, SIRT2-overexpressing NK cells showed a stronger tumoricidal effect on hepatoma cells. Moreover, SIRT2 remarkably promoted the phosphorylation of Extracellular-signal-regulated kinase 1/2 (Erk1/2) and p38 Mitogen-activated protein kinases (MAPK) in activated NK cells. SIRT2 knockdown in liver CD94⁺ NK cells impaired their cytotoxic effect on hepatoma cells. Our study indicates that SIRT2 enhances the tumoricidal activity of liver NK cells in HCC.

Available only for authorised users

Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M (2018) The immunology of hepatocellular carcinoma. Nat Immunol 19:222–232. https://doi.org/10.1038/s41590-018-0044-z CrossRefPubMed

Whiteside TL (2010) Immune responses to malignancies. J Allergy Clin Immunol 125:S272–S283. https://doi.org/10.1016/j.jaci.2009.09.045 CrossRefPubMedPubMedCentral

Muntasell A, Ochoa MC, Cordeiro L, Berraondo P, Lopez-Diaz de Cerio A, Cabo M, Lopez-Botet M, Melero I (2017) Targeting NK-cell checkpoints for cancer immunotherapy. Curr Opin Immunol 45:73–81. https://doi.org/10.1016/j.coi.2017.01.003 CrossRefPubMed

Rezvani K, Rouce RH (2015) The application of natural killer cell immunotherapy for the treatment of cancer. Front Immunol 6:578. https://doi.org/10.3389/fimmu.2015.00578 CrossRefPubMedPubMedCentral

Daher M, Rezvani K (2018) Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering. Curr Opin Immunol 51:146–153. https://doi.org/10.1016/j.coi.2018.03.013 CrossRefPubMedPubMedCentral

Rezvani K, Rouce R, Liu E, Shpall E (2017) Engineering natural killer cells for cancer immunotherapy. Mol Ther 25:1769–1781. https://doi.org/10.1016/j.ymthe.2017.06.012 CrossRefPubMedPubMedCentral

Sidorova-Darmos E, Wither RG, Shulyakova N, Fisher C, Ratnam M, Aarts M, Lilge L, Monnier PP, Eubanks JH (2014) Differential expression of sirtuin family members in the developing, adult, and aged rat brain. Front Aging Neurosci 6:333. https://doi.org/10.3389/fnagi.2014.00333 CrossRefPubMedPubMedCentral

Zhang J, Lee SM, Shannon S et al (2009) The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J Clin Invest 119:3048–3058. https://doi.org/10.1172/JCI3890238902 CrossRefPubMedPubMedCentral

Zou T, Yang Y, Xia F, Huang A, Gao X, Fang D, Xiong S, Zhang J (2013) Resveratrol Inhibits CD4+ T cell activation by enhancing the expression and activity of Sirt1. PLoS One 8:e75139. https://doi.org/10.1371/journal.pone.0075139 CrossRefPubMedPubMedCentral

10.

Beier UH, Wang L, Bhatti TR, Liu Y, Han R, Ge G, Hancock WW (2011) Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol Cell Biol 31:1022–1029. https://doi.org/10.1128/MCB.01206-10 CrossRefPubMedPubMedCentral

11.

van Loosdregt J, Brunen D, Fleskens V, Pals CE, Lam EW, Coffer PJ (2011) Rapid temporal control of Foxp3 protein degradation by sirtuin-1. PLoS One 6:e19047. https://doi.org/10.1371/journal.pone.0019047 CrossRefPubMedPubMedCentral

12.

Kwon HS, Lim HW, Wu J, Schnolzer M, Verdin E, Ott M (2012) Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J Immunol 188:2712–2721. https://doi.org/10.4049/jimmunol.1100903 CrossRefPubMed

13.

Dai K, Huang Y, Chen Z, Sun X, Yang L, Jiang Y (2018) Kbtbd2 inhibits the cytotoxic activity of immortalized NK cells through down-regulating mTOR signaling in a mouse hepatocellular carcinoma model. Eur J Immunol 48:683–695. https://doi.org/10.1002/eji.201747281 CrossRefPubMed

14.

Yu J, Wei M, Mao H et al (2009) CD94 defines phenotypically and functionally distinct mouse NK cell subsets. J Immunol 183:4968–4974. https://doi.org/10.4049/jimmunol.0900907 CrossRefPubMed

15.

Vossen MT, Matmati M, Hertoghs KM, Baars PA, Gent MR, Leclercq G, Hamann J, Kuijpers TW, van Lier RA (2008) CD27 defines phenotypically and functionally different human NK cell subsets. J Immunol 180:3739–3745CrossRefPubMed

16.

Xu H, Li Y, Chen L, Wang C, Wang Q, Zhang H, Lin Y, Li Q, Pang T (2016) SIRT2 mediates multidrug resistance in acute myelogenous leukemia cells via ERK1/2 signaling pathway. Int J Oncol 48:613–623. https://doi.org/10.3892/ijo.2015.3275 CrossRefPubMed

17.

She DT, Wong LJ, Baik SH, Arumugam TV (2018) SIRT2 inhibition confers neuroprotection by downregulation of FOXO3a and MAPK signaling pathways in ischemic stroke. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1058-0 CrossRefPubMed

18.

Fu B, Tian Z, Wei H (2014) Subsets of human natural killer cells and their regulatory effects. Immunology 141:483–489. https://doi.org/10.1111/imm.12224 CrossRefPubMedPubMedCentral

19.

Zhang QF, Yin WW, Xia Y, Yi YY, He QF, Wang X, Ren H, Zhang DZ (2017) Liver-infiltrating CD11b(-)CD27(-) NK subsets account for NK-cell dysfunction in patients with hepatocellular carcinoma and are associated with tumor progression. Cell Mol Immunol 14:819–829. https://doi.org/10.1038/cmi.2016.28 CrossRefPubMed

20.

Bosch-Presegue L, Vaquero A (2014) Sirtuins in stress response: guardians of the genome. Oncogene 33:3764–3775. https://doi.org/10.1038/onc.2013.344 CrossRefPubMed

21.

Buler M, Andersson U, Hakkola J (2016) Who watches the watchmen? Regulation of the expression and activity of sirtuins. FASEB J 30:3942–3960CrossRefPubMed

22.

Anwar T, Khosla S, Ramakrishna G (2016) Increased expression of SIRT2 is a novel marker of cellular senescence and is dependent on wild type p53 status. Cell Cycle 15:1883–1897. https://doi.org/10.1080/15384101.2016.1189041 CrossRefPubMedPubMedCentral

23.

Collin R, St-Pierre C, Guilbault L et al (2017) An unbiased linkage approach reveals that the p53 pathway is coupled to NK cell maturation. J Immunol 199:1490–1504. https://doi.org/10.4049/jimmunol.1600789 CrossRefPubMed

24.

Wu G, Song C, Lu H, Jia L, Yang G, Shi X, Sun S (2014) Sirt2 induces C2C12 myoblasts proliferation by activation of the ERK1/2 pathway. Acta Biochim Biophys Sin (Shanghai) 46:342–345. https://doi.org/10.1093/abbs/gmt151 CrossRef

25.

Jung YJ, Lee AS, Nguyen-Thanh T, Kim D, Kang KP, Lee S, Park SK, Kim W (2015) SIRT2 regulates LPS-induced renal tubular CXCL2 and CCL2 expression. J Am Soc Nephrol 26:1549–1560. https://doi.org/10.1681/ASN.2014030226 CrossRefPubMed

26.

Chen X, Trivedi PP, Ge B, Krzewski K, Strominger JL (2007) Many NK cell receptors activate ERK2 and JNK1 to trigger microtubule organizing center and granule polarization and cytotoxicity. Proc Natl Acad Sci USA 104:6329–6334. https://doi.org/10.1073/pnas.0611655104 CrossRefPubMedPubMedCentral

27.

Trotta R, Fettucciari K, Azzoni L, Abebe B, Puorro KA, Eisenlohr LC, Perussia B (2000) Differential role of p38 and c-Jun N-terminal kinase 1 mitogen-activated protein kinases in NK cell cytotoxicity. J Immunol 165:1782–1789CrossRefPubMed

28.

Yu M, Luo H, Fan M et al (2018) Development of GPC3-specific chimeric antigen receptor-engineered natural killer cells for the treatment of hepatocellular carcinoma. Mol Ther 26:366–378. https://doi.org/10.1016/j.ymthe.2017.12.012 CrossRefPubMed

Title: Sirtuin2 enhances the tumoricidal function of liver natural killer cells in a mouse hepatocellular carcinoma model
Authors: Ming Chen
Min Xu
Chengliang Zhu
Hongling Wang
Qiu Zhao
Feng Zhou
Publication date: 01-06-2019
Publisher: Springer Berlin Heidelberg
Keywords: Hepatocellular Carcinoma
Hepatocellular Carcinoma
Published in: Cancer Immunology, Immunotherapy / Issue 6/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-019-02337-5

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2019

DNA lesions correlate with lymphocyte function after selective internal radiotherapy

Age and sex have no impact on expression levels of markers of immune cell infiltration and immune checkpoint pathways in patients with muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy

Characterization of circulating T-, NK-, and NKT cell subsets in patients with colorectal cancer: the peripheral blood immune cell profile

Heterogeneity of PD-L1 expression and CD8 tumor-infiltrating lymphocytes among subtypes of cutaneous adnexal carcinomas

Systemic and local immunosuppression in patients with high-grade meningiomas

Immune-phenotyping of pleomorphic dermal sarcomas suggests this entity as a potential candidate for immunotherapy

Keynote webinar | Spotlight on antibody–drug conjugates in cancer