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Vol. 64 No. 12: Issue 12

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SMAR1 promotes immune escape of Tri-negative Breast Cancer through a mechanism involving T-bet/PD-1 Axis

https://doi.org/10.14715/cmb/2018.64.12.14
Wang Xiaohua
Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
Xu Hongxia
Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
Deng Rong
Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
Wu Pingping
Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
Huang Xing
Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
Zhu Yichao
Nanjing Medical University, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
Chen Cheng
Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China

Corresponding Author(s) : Wang Xiaohua

zg1274@163.com

Cellular and Molecular Biology, Vol. 64 No. 12: Issue 12

Abstract

This study was aimed at investigating the specific molecular mechanisms involved in the regulation of immune escape of triple-negative breast cancer (TNBC) by SMRI, so as to provide a new clinical treatment target for the disease. Mouse original 4T1 breast cancer cells were inoculated subcutaneously in BALB/C to establish TNBC mouse model. CD8+T cells with immunological effects were selected from mouse thymus glands for primary culture. The CD8+positive T cells were infected with lentivirus interference vectors, and the proliferation of CD8+ T cells were determined by trypan blue staining and flow cytometry. CD8+T cells and 4T1 cells were cultured together so as to determine the cytotoxic effects of SMAR1-downregulated CD8+ T cells on tumor cells and the expression of cytokines (IFN-γ, TNF-α, IL-2, IL-4 and IL-6). The expressions of SMAR1, T-bet and PD-1 were assayed by Western blot. SMAR1-downregulated CD8+T cells were injected into 4T1 tumor-bearing mice through the caudal vein, and the growth of tumor in mice was monitored. Following the infection of CD8+T cells with SMAR1-downregulated lentiviral system, cell apoptosis level was decreased significantly (control vs. sh-SMAR1: 32.23 ± 12.4 % vs. 18.28 ± 8.93 %, p < 0.05). Results from trypan blue staining experiments showed that the proliferation of CD8+ T cells in the SMAR1-downregulated group was significantly increased; SMAR1-downregulated CD8+ T cells promoted the production of IFN-γ, TNF-α, IL-2, IL-4 and IL-6 in 4T1 breast cancer cells (p < 0.05). Western blot showed that SMAR1 down-regulation led to significant upregulation of T-bet, while PD-1 was downregulated, when compared to the control group (p < 0.05). The downregulation of SMAR1 was associated with significant reduction in tumor size in mice (p < 0.05). SMAR1 downregulation enhances the tumor killing effect of CD8+T cells by activating T-bet and down-regulating PD-1

Keywords

SMAR1 T-bet PD-1 Triple negative breast cancer Immune escape.
Xiaohua, W., Hongxia, X., Rong, D., Pingping, W., Xing, H., Yichao, Z., & Cheng, C. (2018). SMAR1 promotes immune escape of Tri-negative Breast Cancer through a mechanism involving T-bet/PD-1 Axis. Cellular and Molecular Biology, 64(12), 70–75. https://doi.org/10.14715/cmb/2018.64.12.14
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References
  1. Rheinbay E, Parasuraman P, Grimsby J, Tiao G, Engreitz JM, Kim J, et al. Recurrent and functional regulatory mutations in breast cancer. Nat 2017; 547: 55-60.
  2. DeSantis CE, Ma J, Goding SA, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 2017; 67: 439-448.
  3. Denkert C, Liedtke C, Tutt A, Von MG. Molecular alterations in triple-negative breast cancer”the road to new treatment strategies. Lancet 2017; 389: 2430-2442.
  4. Quist J, Mirza H, Cheang MCU, Melinda LT, Christopher JL, Andrew NJT. Association of a four-gene decision tree signature with response to platinum-based chemotherapy in patients with triple negative breast cancer. J Clin Oncol 2017; 35: 1006.
  5. Deal K, Nylen E, Barber A E. T cells expressing chimeric PD1 receptors that contain a Dap10 costimulatory domain are a potential treatment for multiple types of cancer. Cancer Res 2017; 77: 4983-4983.
  6. Tran PN, Sarkissian S, Chao J, Klempner SJ. PD-1 and PD-L1 as emerging therapeutic targets in gastric cancer: current evidence. Gastrointest Cancer 2017; 7:1.
  7. Muenst S, Schaerli AR, Gao F, Däster S, Trella E, Droeser RA, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 2014; 146: 15-24.
  8. Duchnowska R, Pć™ksa R, Radecka B, Tomasz M, Tomasz T, Bożena J, et al. Immune response in breast cancer brain metastases and their microenvironment: the role of the PD-1/PD-L axis. Breast Cancer Res 2016; 18: 43.
  9. Paul D, Ghorai S, Dinesh US, Shetty P, Chattopadhyay S, Santra MK. Cdc20 directs proteasome-mediated degradation of the tumor suppressor SMAR1 in higher grades of cancer through the anaphase promoting complex. Cell Death Dis 2017; 8: 2882.
  10. Nakka KK, Chaudhary N, Joshi S, Bhat J, Singh K, Chatterjee S, et al. Nuclear matrix-associated protein SMAR1 regulates alternative splicing via HDAC6-mediated deacetylation of Sam68. Proc Natl Acad Sci U S A 2015; 112: 3374-3383.
  11. Liu H, Ma F, Shen Y, Hu YQ, Pan S. Overexpression of SMAR1 enhances radiosensitivity in human breast cancer cell line MCF7 via activation of p53 signaling pathway. Oncol Res 2014; 22: 293-300.
  12. Mirlekar B, Patil S, Bopanna R, Chattopadhyay S. MAR binding protein SMAR1 favors IL-10 mediated regulatory T cell function in acute colitis. Biochem Biophys Res Commun 2015; 464: 647-653.
  13. Mirlekar B, Ghorai S, Khetmalas M, Bopanna R, Chattopadhyay S. Nuclear matrix protein SMAR1 control regulatory T-cell fate during inflammatory bowel disease (IBD). Mucosal Immunol 2015; 8: 1184.
  14. Chemmannur SV, Badhwar AJ, Mirlekar B, Malonia SK, Gupta M, Wadhwa N, et al. Nuclear matrix binding protein SMAR1 regulates T-cell differentiation and allergic airway disease. Mucosal Immunol 2015; 8: 1201.
  15. Strí¸nen E, Toebes M, Kelderman S, van Buuren MM, Yang W, van Rooij N, et al. Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Sci 2016; 352: 1337-1341.
  16. Reck M, Rodrí­guez-Abreu D, Robinson AG, Hui R, CsÅ‘szi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med 2016; 375: 1823-1833.
  17. Krausgruber T, Schiering C, Adelmann K, Harrison OJ, Chomka A, Pearson C, et al. T-bet is a key modulator of IL-23-driven pathogenic CD4+ T cell responses in the intestine. Nat Commun 2016; 7: 11627.
  18. Daussy C, Faure F, Mayol K, Viel S, Gasteiger G, Charrier E, et al. T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med 2014; 211: 563-77
  19. Taylor A, Harker JA, Chanthong K, Stevenson PG, Zuniga EI, Rudd CE. Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of co-receptor PD-1 to enhance CD8+ cytolytic T cell responses. Immunity 2016; 44: 274-286.
  20. Huang AC, Postow MA, Orlowski RJ, Mick R, Bengsch, Manne S, et al. T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nat 2017; 545: 60-65.
  21. Chamoto K, Chowdhury PS, Kumar A, Sonomura K, Matsuda F, Fagarasan S, et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci U S A 2017; 114: 761-770.
  22. Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 2016; 45: 415-427.
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