The effects of Tim‑3 activation on T‑cells in gastric cancer progression

Yu,Jiangtao; Zhang,Huanhu; Sun,Shengbo; Sun,Shaowei; Li,Leping

doi:10.3892/ol.2018.9743

The effects of Tim‑3 activation on T‑cells in gastric cancer progression

Authors:
- Jiangtao Yu
- Huanhu Zhang
- Shengbo Sun
- Shaowei Sun
- Leping Li
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Affiliations: Department of Gastrointestinal Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Department of Gastrointestinal Surgery, Weihai Municipal Hospital, Weihai, Shandong 264200, P.R. China
Published online on: November 21, 2018 https://doi.org/10.3892/ol.2018.9743
Pages: 1461-1466
Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The incidence of gastric cancer is high, especially in China. The present study aims to provide a novel therapeutic target for gastric cancer. Peripheral blood, cancerous and paracancerous tissues were collected from patients with gastric cancer. T‑cell immunoglobulin mucin domain‑3 (Tim‑3) expression in T‑cells was measured and the correlation between Tim‑3 expression and the T staging of gastric cancer was analyzed. The levels of T‑cell secreted interferon (IFN)‑γ and tumor necrosis factor (TNF)‑α were assessed following Tim‑3 signaling pathway activation. A nude mouse model of gastric cancer was established and Tim‑3‑stimulated T‑cells were injected into the mice to evaluate tumor growth. The results of the present study demonstrated that Tim‑3 expression levels from the paracancerous and cancerous gastric tissues were significantly increased compared with the peripheral blood, while its expression was significantly increased in cancerous compared with paracancerous gastric tissues. With the T staging of gastric cancer increasing, the expression of Tim‑3 gradually increased. The activation of the Tim‑3 signaling pathway in T‑cells may inhibit IFN‑γ and TNF‑α secretion, and the results from the nude mice tumor model demonstrated that the inhibitory effect on tumor growth by T‑cells was reduced by Tim‑3 signaling pathway activation. The expression level of Tim‑3 on the surface of tumor infiltrating T‑cells in gastric cancer tissue increases significantly and the increased Tim‑3 signaling may inhibit the function of T‑cells. The results suggest that the increased expression of Tim‑3 on T‑cells may be involved the development of gastric cancer.

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1	Cheng G, Li M, Wu J, Ji M, Fang C, Shi H, Zhu D, Chen L, Zhao J, Shi L, et al: Expression of Tim-3 in gastric cancer tissue and its relationship with prognosis. Int J Clin Exp Pathol. 8:9452–9457. 2015.PubMed/NCBI
2	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
3	Moore MA, Eser S, Igisinov N, Igisinov S, Mohagheghi MA, Mousavi-Jarrahi A, Ozentürk G, Soipova M, Tuncer M and Sobue T: Cancer epidemiology and control in North-Western and Central Asia-past, present and future. Asian Pac J Cancer Prev. 11 Suppl 2:S17–S32. 2010.
4	Qiu MZ, Wang ZQ, Zhang DS, Liu Q, Luo HY, Zhou ZW, Li YH, Jiang WQ and Xu RH: Comparison of 6th and 7th AJCC TNM staging classification for carcinoma of the stomach in China. Ann Surg Oncol. 18:1869–1876. 2011. View Article : Google Scholar : PubMed/NCBI
5	Park JM, Kim JH, Park SS, Kim SJ, Mok YJ and Kim CS: Prognostic factors and availability of D2 lymph node dissection for the patients with stage II gastric cancer: Comparative analysis of subgroups in stage II. World J Surg. 32:1037–1044. 2008. View Article : Google Scholar : PubMed/NCBI
6	Jin Y, Qiu MZ, Wang DS, Zhang DS, Ren C, Bai L, Luo HY, Wang ZQ, Wang FH, Li YH, et al: Adjuvant chemotherapy for elderly patients with gastric cancer after D2 gastrectomy. PLoS One. 8:e531492013. View Article : Google Scholar : PubMed/NCBI
7	Takano S, Saito H and Ikeguchi M: An increased number of PD-1⁺ and Tim-3⁺ CD8⁺ T-cells is involved in immune evasion in gastric cancer. Surg Today. 46:1341–1347. 2016. View Article : Google Scholar : PubMed/NCBI
8	Hassan SS, Akram M, King EC, Dockrell HM and Cliff JM: PD-1, PD-L1 and PD-L2 gene expression on t-cells and natural killer cells declines in conjunction with a reduction in PD-1 protein during the intensive phase of tuberculosis treatment. PLoS One. 10:e01376462015. View Article : Google Scholar : PubMed/NCBI
9	Lee KA, Shin KS, Kim GY, Song YC, Bae EA, Kim IK, Koh CH and Kang CY: Characterization of age-associated exhausted CD8⁺ T-cells defined by increased expression of Tim-3 and PD-1. Aging Cell. 15:291–300. 2016. View Article : Google Scholar : PubMed/NCBI
10	Park HJ, Park JS, Jeong YH, Son J, Ban YH, Lee BH, Chen L, Chang J, Chung DH, Choi I, et al: Correction: PD-1 upregulated on regulatory T-cells during chronic virus infection enhances the suppression of CD8⁺ T-cell immune response via the interaction with PD-L1 expressed on CD8⁺ T-cells. J Immunol. 195:5841–5842. 2015. View Article : Google Scholar : PubMed/NCBI
11	Ngiow SF, von Scheidt B, Akiba H, Yagita H, Teng MW and Smyth MJ: Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res. 71:3540–3551. 2011. View Article : Google Scholar : PubMed/NCBI
12	Yuan L, Xu B, Yuan P, Zhou J, Qin P, Han L, Chen G, Wang Z, Run Z, Zhao P, et al: Tumor-infiltrating CD4⁺ T-cells in patients with gastric cancer. Cancer Cell Int. 17:1142017. View Article : Google Scholar : PubMed/NCBI
13	McIntire JJ, Umetsu SE, Akbari O, Potter M, Kuchroo VK, Barsh GS, Freeman GJ, Umetsu DT and DeKruyff RH: Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family. Nat Immunol. 2:1109–1116. 2001. View Article : Google Scholar : PubMed/NCBI
14	Shakhov AN, Rybtsov S, Tumanov AV, Shulenin S, Dean M, Kuprash DV and Nedospasov SA: SMUCKLER/TIM4 is a distinct member of TIM family expressed by stromal cells of secondary lymphoid tissues and associated with lymphotoxin signaling. Eur J Immunol. 34:494–503. 2004. View Article : Google Scholar : PubMed/NCBI
15	Markwick LJ, Riva A, Ryan JM, Cooksley H, Palma E, Tranah TH, Manakkat Vijay GK, Vergis N, Thursz M, Evans A, et al: Blockade of PD1 and TIM3 restores innate and adaptive immunity in patients with acute alcoholic hepatitis. Gastroenterology. 148:590–602. 2015. View Article : Google Scholar : PubMed/NCBI
16	Tao JL, Li LJ, Fu R, Wang HQ, Jiang HJ, Yue LZ, Zhang W, Liu H, Ruan EB, Qu W, et al: Elevated TIM3⁺ hematopoietic stem cells in untreated myelodysplastic syndrome displayed aberrant differentiation, overproliferation and decreased apoptosis. Leuk Res. 38:714–721. 2014. View Article : Google Scholar : PubMed/NCBI
17	Roth CG, Garner K, Eyck ST, Boyiadzis M, Kane LP and Craig FE: TIM3 expression by leukemic and non-leukemic myeloblasts. Cytometry B Clin Cytom. 84:167–172. 2013. View Article : Google Scholar : PubMed/NCBI
18	Ge RT, Zeng L, Mo LH, Xu LZ, Zhang HP, Yu HQ, Zhang M, Liu ZG, Liu ZJ and Yang PC: Interaction of TIM4 and TIM3 induces T helper 1 cell apoptosis. Immunol Res. 64:470–475. 2016. View Article : Google Scholar : PubMed/NCBI
19	Ma Y, Liu X, Zhu J, Li W, Guo L, Han X, Song B, Cheng S and Jie L: Polymorphisms of co-inhibitory molecules (CTLA-4/PD-1/PD-L1) and the risk of non-small cell lung cancer in a Chinese population. Int J Clin Exp Med. 8:16585–16591. 2015.PubMed/NCBI
20	Li Z, Li N, Zhu Q, Zhang G, Han Q, Zhang P, Xun M, Wang Y, Zeng X, Yang C, et al: Genetic variations of PD1 and TIM3 are differentially and interactively associated with the development of cirrhosis and HCC in patients with chronic HBV infection. Infect Genet Evol. 14:240–246. 2013. View Article : Google Scholar : PubMed/NCBI
21	Ngiow SF, Teng MW and Smyth MJ: Prospects for TIM3-targeted antitumor immunotherapy. Cancer Res. 71:6567–6571. 2011. View Article : Google Scholar : PubMed/NCBI
22	Jayaraman P, Sada-Ovalle I, Beladi S, Anderson AC, Dardalhon V, Hotta C, Kuchroo VK and Behar SM: Tim3 binding to galectin-9 stimulates antimicrobial immunity. J Exp Med. 207:2343–2354. 2010. View Article : Google Scholar : PubMed/NCBI
23	Bu M, Shen Y, Seeger WL, An S, Qi R, Sanderson JA and Cai Y: Ovarian carcinoma-infiltrating regulatory T-cells were more potent suppressors of CD8(+) T-cell inflammation than their peripheral counterparts, a function dependent on TIM3 expression. Tumour Biol. 37:3949–3956. 2016. View Article : Google Scholar : PubMed/NCBI
24	Oomizu S, Arikawa T, Niki T, Kadowaki T, Ueno M, Nishi N, Yamauchi A and Hirashima M: Galectin-9 suppresses Th17 cell development in an IL-2-dependent but Tim-3-independent manner. Clin Immunol. 143:51–58. 2012. View Article : Google Scholar : PubMed/NCBI