T‑cell immunoglobulin and mucin domain‑containing protein‑3 and galectin‑9 protein expression: Potential prognostic significance in esophageal squamous cell carcinoma for Chinese patients

Hou,Nan; Ma,Jie; Li,Wei; Zhao,Lingdi; Gao,Quanli; Mai,Ling

doi:10.3892/ol.2017.7188

T‑cell immunoglobulin and mucin domain‑containing protein‑3 and galectin‑9 protein expression: Potential prognostic significance in esophageal squamous cell carcinoma for Chinese patients

Authors:
- Nan Hou
- Jie Ma
- Wei Li
- Lingdi Zhao
- Quanli Gao
- Ling Mai
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Affiliations: Department of Biological Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450003, P.R. China, Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450003, P.R. China, Institute of Cancer Research, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan 450003, P.R. China
Published online on: October 16, 2017 https://doi.org/10.3892/ol.2017.7188
Pages: 8007-8013
Copyright: © Hou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to investigate the expression levels of the T‑cell immunoglobulin and mucin domain‑containing protein‑3 (TIM‑3) and galectin‑9 proteins and their clinical value in esophageal squamous cell carcinoma (ESCC) in Chinese patients. The expression profiles of TIM‑3 and galectin‑9 in ESCC were determined by the immunohistochemical analysis of the postoperative pathological specimens of 45 patients with ESCC; a χ2 test was used to evaluate the association of TIM‑3 and galectin‑9 expression with clinicopathological parameters, in addition to univariate and multivariate Cox's proportional hazards model to analyze the prognostic value of the expression of TIM‑3 and galectin‑9 proteins. The proportion of samples exhibiting a high staining intensity for TIM‑3 and galectin‑9 were 22.22 and 15.56%, respectively: these samples were termed the TIM‑3 high‑expression group (HEG) and galectin‑9‑HEG. There was a negative correlation between the expression of TIM‑3 and galectin‑9 (R=‑0.71, P<0.001). The results of Kaplan‑Meier survival analysis led to the conclusion that, compared with the TIM‑3 low expression group (LEG), patients in the TIM‑3‑HEG exhibited a poorer overall survival rate (χ2=6.049, P=0.0139). By contrast, patients in the galectin‑9‑HEG exhibited a significantly better overall survival rate than those in the galectin‑9‑LEG (χ2=4.915, P=0.0266). However, the levels of TIM‑3 and galectin‑9 expression were not identified as independent indicators for the prognosis of patients with ESCC. As high TIM‑3 and low galectin‑9 expression levels were associated with a poor prognosis for patients with ESCC in the present study, these proteins may be potential prognostic indicators for ESCC.

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1	Domper Arnal MJ, Ferrández Arenas Á and Lanas Arbeloa Á: Esophageal cancer: Risk factors, screening and endoscopic treatment in Western and Eastern countries. World J Gastroenterol. 21:7933–7943. 2015. View Article : Google Scholar : PubMed/NCBI
2	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
3	Napier KJ, Scheerer M and Misra S: Esophageal cancer: A review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 6:112–120. 2014. View Article : Google Scholar : PubMed/NCBI
4	Pennathur A, Gibson MK, Jobe BA and Luketich JD: Oesophageal carcinoma. Lancet. 381:400–412. 2013. View Article : Google Scholar : PubMed/NCBI
5	Chen W, Zheng R, Zhang S, Zhao P, Li G, Wu L and He J: The incidences and mortalities of major cancers in China, 2009. Chin J Cancer. 32:106–112. 2013. View Article : Google Scholar : PubMed/NCBI
6	Xie J, Wang J, Cheng Sh, Zheng L, Ji F, Yang L, Zhang Y and Ji H: Expression of immune checkpoints in T cells of esophageal cancer patients. Oncotarget. 27:63669–63678. 2016. View Article : Google Scholar
7	Pardoll DM: The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 12:252–264. 2012. View Article : Google Scholar : PubMed/NCBI
8	Qiu H, Zheng L, Tang W, Yin P, Cheng F and Wang L: Programmed death-1 (PD-1) polymorphisms in Chinese patients with esophageal cancer. Clin Biochem. 47:612–617. 2014. View Article : Google Scholar : PubMed/NCBI
9	Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, et al: Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 415:536–541. 2002. View Article : Google Scholar : PubMed/NCBI
10	Cao E, Zang X, Ramagopal UA, Mukhopadhaya A, Fedorov A, Fedorov E, Zencheck WD, Lary JW, Cole JL, Deng H, et al: T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity. 26:311–321. 2007. View Article : Google Scholar : PubMed/NCBI
11	Santiago C, Ballesteros A, Martínez-Muñoz L, Mellado M, Kaplan GG, Freeman GJ and Casasnovas JM: Structures of T cell immunoglobulin mucin protein 4 show a metal-Ion-dependent ligand binding site where phosphatidylserine binds. Immunity. 27:941–951. 2007. View Article : Google Scholar : PubMed/NCBI
12	Santiago C, Ballesteros A, Tami C, Martínez-Muñoz L, Kaplan GG and Casasnovas JM: Structures of T Cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the TIM receptor family. Immunity. 26:299–310. 2007. View Article : Google Scholar : PubMed/NCBI
13	Xu B, Yuan L, Gao Q, Yuan P, Zhao P, Yuan H, Fan H, Li T, Qin P, Han L, et al: Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer. Oncotarget. 6:20592–20603. 2015. View Article : Google Scholar : PubMed/NCBI
14	Freeman GJ, Casasnovas JM, Umetsu DT and DeKruyff RH: TIM genes: A family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev. 235:172–189. 2010. View Article : Google Scholar : PubMed/NCBI
15	Nicodemus CF: Antibody-based immunotherapy of solid cancers: Progress and possibilities. Immunotherapy. 7:923–939. 2015. View Article : Google Scholar : PubMed/NCBI
16	Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, Murphy WJ, Azuma M, Anderson AC, Kuchroo VK and Blazar BR: Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 117:4501–4510. 2011. View Article : Google Scholar : PubMed/NCBI
17	Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, Kirkwood JM, Kuchroo V and Zarour HM: Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 207:2175–2186. 2010. View Article : Google Scholar : PubMed/NCBI
18	Sakuishi K, Ngiow SF, Sullivan JM, Teng MW, Kuchroo VK, Smyth MJ and Anderson AC: TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. Oncoimmunology. 2:e238492013. View Article : Google Scholar : PubMed/NCBI
19	Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK and Anderson AC: Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 207:2187–2194. 2010. View Article : Google Scholar : PubMed/NCBI
20	Tarhini A: Immune-mediated adverse events associated with ipilimumab ctla-4 blockade therapy: The underlying mechanisms and clinical management. Scientifica (Cairo). 2013:8575192013.PubMed/NCBI
21	Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ, Kefford R, Wolchok JD, Hersey P, Joseph RW, Weber JS, et al: Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 369:134–144. 2013. View Article : Google Scholar : PubMed/NCBI
22	Anderson AC: Tim-3: An emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2:393–398. 2014. View Article : Google Scholar : PubMed/NCBI
23	Cao Y, Zhou X, Huang X, Li Q, Gao L, Jiang L, Huang M and Zhou J: Tim-3 expression in cervical cancer promotes tumor metastasis. PLoS One. 8:e538342013. View Article : Google Scholar : PubMed/NCBI
24	Jiang J, Jin MS, Kong F, Cao D, Ma HX, Jia Z, Wang YP, Suo J and Cao X: Decreased galectin-9 and increased Tim-3 expression are related to poor prognosis in gastric cancer. PLoS One. 8:e817992013. View Article : Google Scholar : PubMed/NCBI
25	Ferris RL, Lu B and Kane LP: Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion. J Immunol. 193:1525–1530. 2014. View Article : Google Scholar : PubMed/NCBI
26	Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, Zheng XX, Strom TB and Kuchroo VK: The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 6:1245–1252. 2005. View Article : Google Scholar : PubMed/NCBI
27	Su EW, Bi S and Kane LP: Galectin-9 regulates T helper cell function independently of Tim-3. Glycobiology. 21:1258–1265. 2011. View Article : Google Scholar : PubMed/NCBI
28	Leitner J, Rieger A, Pickl WF, Zlabinger G, Grabmeier-Pfistershammer K and Steinberger P: TIM-3 does not act as a receptor for galectin-9. PLoS Pathog. 9:e10032532013. View Article : Google Scholar : PubMed/NCBI
29	Sakuishi K, Jayaraman P, Behar SM, Anderson AC and Kuchroo VK: Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol. 32:345–349. 2011. View Article : Google Scholar : PubMed/NCBI
30	National Comprehensive Cancer Network: (NCCN) Clinical Practice Guidelines in Oncology. Esophageal Cancer. Version 1. 2009, https://www.nccn.org/professionals/physician_gls/f_guidelines.asp
31	Sobin LH, Gospodarowicz MK and Wittekind C: International Union Against Cancer (eds): Title section/chapterTNM Classification of Malignant Tumours. 7th edition. Wiley-Blackwell; Hoboken, NJ: pp. 4552009
32	Irie A, Yamauchi A, Kontani K, Kihara M, Liu D, Shirato Y, Seki M, Nishi N, Nakamura T, Yokomise H and Hirashima M: Galectin-9 as a prognostic factor with antimetastatic potential in breast cancer. Clin Cancer Res. 11:2962–2968. 2005. View Article : Google Scholar : PubMed/NCBI
33	Zhou E, Huang Q, Wang J, Fang C, Yang L, Zhu M, Chen J, Chen L and Dong M: Up-regulation of Tim-3 is associated with poor prognosis of patients with colon cancer. Int J Clin Exp Pathol. 8:8018–8027. 2015.PubMed/NCBI
34	Zhao ZF, Li JX, Ye R, Wu X, Gao LL and Niu BL: Interleukin-6 as a potential molecular target in esophageal squamous cell carcinoma. Oncol Lett. 11:925–932. 2016.PubMed/NCBI
35	Guan C, Zhang J, Zhang J, Shi H and Ni R: Enhanced expression of early mitotic inhibitor-1 predicts a poor prognosis in esophageal squamous cell carcinoma patients. Oncol Lett. 12:114–120. 2016.PubMed/NCBI
36	Wang S, Wang Z, Yang YU, Shi MO and Sun Z: Overexpression of Ku80 correlates with aggressive clinicopathological features and adverse prognosis in esophageal squamous cell carcinoma. Oncol Lett. 10:2705–2712. 2015.PubMed/NCBI
37	Feng Z, Xiang-Lei L, Hai-Tao W, Zuo-Pei W, Bao-Li H, Hai-Feng Z, Xiao-Long W and Li L: Programmed cell death 1 expression in esophageal squamous cell carcinoma and association with clinical characteristics. Indian J Cancer. 52 Suppl 3:E176–E178. 2015. View Article : Google Scholar : PubMed/NCBI
38	Jackie Oh S, Han S, Lee W and Lockhart AC: Emerging immunotherapy for the treatment of esophageal cancer. Expert Opin Investig Drugs. 25:667–677. 2016. View Article : Google Scholar : PubMed/NCBI