负性共刺激分子TIM-3在人非小细胞肺癌T细胞和MDSCs上的表达及意义
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摘要
肿瘤是一个包含有肿瘤细胞、浸润的免疫细胞与间质细胞，以及微环境中一系列分子组成的生态系统。在肿瘤微环境中，浸润的免疫细胞是肿瘤发生发展的重要因素之一。效应T细胞、调节性T细胞、无能T细胞、耗竭性T细胞、巨噬细胞、粒细胞和髓系来源抑制细胞（MDSC）等免疫细胞的浸润在肿瘤微环境中发挥不同的作用，影响着肿瘤进展的全过程。
近年对肿瘤微环境和肿瘤免疫逃逸机制的深入研究发现，一组介导免疫调节的重要负性共刺激分子——免疫卡控点（immune checkpoints），如负性B7家族分子、CTLA-4和TIM-3等，异常表达在一系列肿瘤组织和/或浸润的免疫细胞，参与肿瘤免疫逃逸，并与肿瘤临床病理和预后密切相关，是构成肿瘤微环境的重要成分。
TIM-3， T细胞免疫球蛋白粘蛋白分子（T cell immunoglobulin-andmucin-domain-containing molecules，TIM）家族的一员，主要表达在分化成熟的Th1细胞，细胞毒性CD8+T细胞、单核细胞、树突状细胞等，也被认为是应答性CD8+T细胞耗竭/功能障碍的重要标志性分子之一，而其在肿瘤免疫中的作用则正越来越受到关注。
肿瘤发展的不同阶段，肿瘤微环境浸润的T淋巴细胞亚群和抑制性免疫细胞（如MDSC）借助其表达的负性共刺激分子/免疫卡控点介导抗肿瘤的免疫应答和肿瘤免疫逃逸。深入探讨负性共刺激分子TIM-3在肿瘤浸润T淋巴细胞（TIL）和髓系来源抑制细胞（MDSC）的表达特征、与临床的相关性及其参与肿瘤免疫逃逸的机制可为以干预TIM-3信号为基础的肿瘤免疫治疗提供新的理论基础和靶点。
【目的】探讨负性共刺激分子TIM-3在人非小细胞肺癌T细胞和髓系来源抑制细胞（MDSC）上的表达及其临床意义。
【方法】收集51例手术切除的诊断明确的非小细胞肺癌（NSCLC）病人癌组织及癌旁组织，采用消化液消化和机械研磨的方法获取单细胞悬液，经淋巴细胞分层液分离，经免疫荧光标记和流式细胞仪分析检测TIM-3在肿瘤浸润T淋巴细胞和MDSC的表达。同时采集同一患者和健康志愿者外周血，进行免疫荧光标记并溶血，经流式细胞仪分析检测TIM-3在外周血T淋巴细胞和MDSC的表达。分析TIM-3在非小细胞肺癌患者T细胞的表达与患者临床病理因素之间的相关性。
【结果】（1）与癌旁正常组织浸润淋巴细胞和外周血T细胞相比，非小细胞肺癌患者肿瘤组织浸润淋巴细胞（TILs）表面TIM-3的表达明显上调；（2）统计学分析显示，TIM-3分子在NSCLC患者肿瘤组织浸润CD4+T淋巴细胞的表达与淋巴结转移及患者分期有关；（3）与健康对照组相比，非小细胞肺癌患者外周血MDSC高表达负性共刺激分子TIM-3；与癌旁组织相比，TIM-3在同一患者肿瘤组织的表达也明显上调。
【结论】TIM-3在非小细胞肺癌患者肿瘤浸润CD4+和CD8+T淋巴细胞上有较高的表达，并且其在非小细胞肺癌肿瘤浸润CD4+T细胞的表达与肿瘤的淋巴结转移及患者分期有关。非小细胞肺癌患者外周血和肿瘤组织MDSC也表达负性共刺激分子TIM-3。所获结果为进一步探讨TIM-3分子在肿瘤微环境中的负性调控作用提供了新的思路和机制。
Tumor is a kind of ecosystem consisting of tumor cells, infiltration of immune cellsand stromal cells and the a series of molecules in microenvironment. Infiltratingimmune cells in the tumor microenvironment is one of the important factors for thedevelopment of tumors. infiltration of immune cells including effector T cells,regulatory T cells, anergic T cells, exhausted T cells, macrophages, granulocytes andmyeloid-derived suppressor cells (MDSC) in the tumor microenvironment play adifferent role and affect the whole process of tumor progression.
In-depth study of the tumor microenvironment and tumor immune escapemechanisms in recent years, a group of negative costimulatory molecules mediatingimmune regulation were found and were called immune checkpoints, such as negativeB7family molecules, CTLA-4, TIM-3and so on. Those molecules abnormallyexpressed on a range of tumor tissue and/or infiltrating immune cells involving intumor immune escape, and closely related with clinical pathology and prognosis,constitute an important component of the tumor microenvironment.
TIM-3, a number of the TIM family(T cell immunoglobulin andmucin-domain-containing molecules), mainly expressed on the differentiated Th1cellsand cytotoxic CD8+T cells, monocytes, cells, dendritic cells, is also considered to be animportant marker of the CD8+T cell exhaustion/anergy, and its role in tumor immunityis getting more and more attention.
In different stages of tumor development, infiltrating T lymphocyte subsets andinhibitory immune cells (such as MDSC) in tumor microenvironment by expressingimmune checkpoints mediate anti-tumor immune response and tumor immune escape.The deeply research of expression characteristics of negative costimulatory moleculeTIM-3on infiltrating T lymphocyte subsets and myeloid-derived suppressor cells, therelevance to clinical factor and their participation in tumor immune escape mechanismcan provide a new theoretical basis and target for tumor immunotherapy based onintervention TIM-3signaling pathways.
Objective: To explore the expression and clinical significance of negativecostimulatory molecules TIM-3on non-small cell lung cancer T cells andmyeloid-derived suppressor cells.
Methods: Obtain cancer tissues and adjacent cancer tissues surgical removed from51non-small cell lung cancer (NSCLC) patients. By digesting and mechanicalpulverizing obtain a single cell suspension. Using lymphocyte separation medium getmononuclear cells.By immunofluorescence and flow cytometry detect TIM-3’sexpression on tumor-infiltrating T lymphocytes and MDSC. At the same time collectedthe same patients and healthy volunteers’ peripheral blood.Byimmunofluorescence,hemolysis and flow cytometry detect TIM-3’s expression onperipheral blood T lymphocytes and MDSC. Analysis the relevance between TIM-3’sexpression on non-small cell lung cancer patients’ T-cell and clinicopathological factors.
Results:(1) Compared to adjacent normal tissue-infiltrating lymphocytes andperipheral blood T cells, expression of TIM-3were significantly increased on tumortissue TILs surface in patients with non-small cell lung cancer;(2) Statistical analysisshowed that the expression of TIM-3molecules on tumor-infiltrating CD4+Tlymphocytesin patients with NSCLC is correlated with lymph node metastasis and stage;(3) Compared to healthy controls,MDSC in peripheral blood of patients with non-smallcell lung cancer highly expressed negative costimulatory molecule TIM-3; Comparedto adjacent tissues, expression of TIM-3was also significantly up-regulated in thetumor tissue of the same patient.
Conclusion: TIM-3on tumor infiltrating CD4+and CD8+T lymphocytesin inpatients with non-small cell lung cancer have high expression and TIM-3on tumorinfiltrating CD4+T cells in non-small cell lung cancer is correlated with tumor lymphnode metastasis and patient’s pathological stage.MDSC in peripheral blood and tumortissue of patients with non-small cell lung cancer highly expressed negativecostimulatory molecule TIM-3.The results obtained provide new ideas and mechanismsto further explore the negative regulatory role of TIM-3molecules in the tumormicroenvironment.
近年对肿瘤微环境和肿瘤免疫逃逸机制的深入研究发现，一组介导免疫调节的重要负性共刺激分子——免疫卡控点（immune checkpoints），如负性B7家族分子、CTLA-4和TIM-3等，异常表达在一系列肿瘤组织和/或浸润的免疫细胞，参与肿瘤免疫逃逸，并与肿瘤临床病理和预后密切相关，是构成肿瘤微环境的重要成分。
TIM-3， T细胞免疫球蛋白粘蛋白分子（T cell immunoglobulin-andmucin-domain-containing molecules，TIM）家族的一员，主要表达在分化成熟的Th1细胞，细胞毒性CD8+T细胞、单核细胞、树突状细胞等，也被认为是应答性CD8+T细胞耗竭/功能障碍的重要标志性分子之一，而其在肿瘤免疫中的作用则正越来越受到关注。
肿瘤发展的不同阶段，肿瘤微环境浸润的T淋巴细胞亚群和抑制性免疫细胞（如MDSC）借助其表达的负性共刺激分子/免疫卡控点介导抗肿瘤的免疫应答和肿瘤免疫逃逸。深入探讨负性共刺激分子TIM-3在肿瘤浸润T淋巴细胞（TIL）和髓系来源抑制细胞（MDSC）的表达特征、与临床的相关性及其参与肿瘤免疫逃逸的机制可为以干预TIM-3信号为基础的肿瘤免疫治疗提供新的理论基础和靶点。
【目的】探讨负性共刺激分子TIM-3在人非小细胞肺癌T细胞和髓系来源抑制细胞（MDSC）上的表达及其临床意义。
【方法】收集51例手术切除的诊断明确的非小细胞肺癌（NSCLC）病人癌组织及癌旁组织，采用消化液消化和机械研磨的方法获取单细胞悬液，经淋巴细胞分层液分离，经免疫荧光标记和流式细胞仪分析检测TIM-3在肿瘤浸润T淋巴细胞和MDSC的表达。同时采集同一患者和健康志愿者外周血，进行免疫荧光标记并溶血，经流式细胞仪分析检测TIM-3在外周血T淋巴细胞和MDSC的表达。分析TIM-3在非小细胞肺癌患者T细胞的表达与患者临床病理因素之间的相关性。
【结果】（1）与癌旁正常组织浸润淋巴细胞和外周血T细胞相比，非小细胞肺癌患者肿瘤组织浸润淋巴细胞（TILs）表面TIM-3的表达明显上调；（2）统计学分析显示，TIM-3分子在NSCLC患者肿瘤组织浸润CD4+T淋巴细胞的表达与淋巴结转移及患者分期有关；（3）与健康对照组相比，非小细胞肺癌患者外周血MDSC高表达负性共刺激分子TIM-3；与癌旁组织相比，TIM-3在同一患者肿瘤组织的表达也明显上调。
【结论】TIM-3在非小细胞肺癌患者肿瘤浸润CD4+和CD8+T淋巴细胞上有较高的表达，并且其在非小细胞肺癌肿瘤浸润CD4+T细胞的表达与肿瘤的淋巴结转移及患者分期有关。非小细胞肺癌患者外周血和肿瘤组织MDSC也表达负性共刺激分子TIM-3。所获结果为进一步探讨TIM-3分子在肿瘤微环境中的负性调控作用提供了新的思路和机制。
Tumor is a kind of ecosystem consisting of tumor cells, infiltration of immune cellsand stromal cells and the a series of molecules in microenvironment. Infiltratingimmune cells in the tumor microenvironment is one of the important factors for thedevelopment of tumors. infiltration of immune cells including effector T cells,regulatory T cells, anergic T cells, exhausted T cells, macrophages, granulocytes andmyeloid-derived suppressor cells (MDSC) in the tumor microenvironment play adifferent role and affect the whole process of tumor progression.
In-depth study of the tumor microenvironment and tumor immune escapemechanisms in recent years, a group of negative costimulatory molecules mediatingimmune regulation were found and were called immune checkpoints, such as negativeB7family molecules, CTLA-4, TIM-3and so on. Those molecules abnormallyexpressed on a range of tumor tissue and/or infiltrating immune cells involving intumor immune escape, and closely related with clinical pathology and prognosis,constitute an important component of the tumor microenvironment.
TIM-3, a number of the TIM family(T cell immunoglobulin andmucin-domain-containing molecules), mainly expressed on the differentiated Th1cellsand cytotoxic CD8+T cells, monocytes, cells, dendritic cells, is also considered to be animportant marker of the CD8+T cell exhaustion/anergy, and its role in tumor immunityis getting more and more attention.
In different stages of tumor development, infiltrating T lymphocyte subsets andinhibitory immune cells (such as MDSC) in tumor microenvironment by expressingimmune checkpoints mediate anti-tumor immune response and tumor immune escape.The deeply research of expression characteristics of negative costimulatory moleculeTIM-3on infiltrating T lymphocyte subsets and myeloid-derived suppressor cells, therelevance to clinical factor and their participation in tumor immune escape mechanismcan provide a new theoretical basis and target for tumor immunotherapy based onintervention TIM-3signaling pathways.
Objective: To explore the expression and clinical significance of negativecostimulatory molecules TIM-3on non-small cell lung cancer T cells andmyeloid-derived suppressor cells.
Methods: Obtain cancer tissues and adjacent cancer tissues surgical removed from51non-small cell lung cancer (NSCLC) patients. By digesting and mechanicalpulverizing obtain a single cell suspension. Using lymphocyte separation medium getmononuclear cells.By immunofluorescence and flow cytometry detect TIM-3’sexpression on tumor-infiltrating T lymphocytes and MDSC. At the same time collectedthe same patients and healthy volunteers’ peripheral blood.Byimmunofluorescence,hemolysis and flow cytometry detect TIM-3’s expression onperipheral blood T lymphocytes and MDSC. Analysis the relevance between TIM-3’sexpression on non-small cell lung cancer patients’ T-cell and clinicopathological factors.
Results:(1) Compared to adjacent normal tissue-infiltrating lymphocytes andperipheral blood T cells, expression of TIM-3were significantly increased on tumortissue TILs surface in patients with non-small cell lung cancer;(2) Statistical analysisshowed that the expression of TIM-3molecules on tumor-infiltrating CD4+Tlymphocytesin patients with NSCLC is correlated with lymph node metastasis and stage;(3) Compared to healthy controls,MDSC in peripheral blood of patients with non-smallcell lung cancer highly expressed negative costimulatory molecule TIM-3; Comparedto adjacent tissues, expression of TIM-3was also significantly up-regulated in thetumor tissue of the same patient.
Conclusion: TIM-3on tumor infiltrating CD4+and CD8+T lymphocytesin inpatients with non-small cell lung cancer have high expression and TIM-3on tumorinfiltrating CD4+T cells in non-small cell lung cancer is correlated with tumor lymphnode metastasis and patient’s pathological stage.MDSC in peripheral blood and tumortissue of patients with non-small cell lung cancer highly expressed negativecostimulatory molecule TIM-3.The results obtained provide new ideas and mechanismsto further explore the negative regulatory role of TIM-3molecules in the tumormicroenvironment.
引文
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[1] Monney L.Th1-specific cell surfaceprotein TIM-3regulates macrophageactivationand severity of an autoimmune disease[J].Nature,2002,415:536-541.
[2] Nakae S,Iikura M,Suto H.et al.TIM-1andTIM-3enhancement of Th2cytokineproduction by mastcells[J].Blood,2007,110:2565-2568.
[3] Cua DJ,Sherloc kJ, Chen Y,Murphy CA.et al. Interleukin-23rather thaninterleukin-12is the critical cytokine for autoimmune inflammation of thebrain[J].Nature,2003,421:744-748.
[4] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expressed on innate immunecells[J].Science,2007,318:1141-1143.
[5] Wang F,He W,Zhou H,.et al.The TIM-3ligand galectin-9negatively regulatesCD8+alloreactive T cell and prolongs survival of skin graft[J]. CellImmunol.2007,250:68-74.
[6] Dardalhon V,Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11b+Ly-6G+myeloidcells[J]. J Immunol.2010,185(3):1383-1392.
[7] Sui L, ZhangW, Chen Y, et al. Human membrane protein TIM23facilitateshepatitis Avirus entry into target cell [J]. Int J Mol Med,2006,17(6):109321099.
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[14] Dardalhon V, Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11bLy-6G myeloid cells[J]. JImmunol2010,185:1383-1392.
[15] Ghansah T. A novel strategy for modulation of MDSC to enhance cancerimmunotherapy[J].Oncoimmunology,2012,1(6):984-985.
[16] Yu J, Du W, Yan F,et al.Myeloid-Derived Suppressor Cells SuppressAntitumor Immune Responses through IDO Expression and Correlate with LymphNode Metastasis in Patients with Breast Cancer[J].J Immunol.,2013,190(7):3783-3797.
[1] Kim PS, Ahmed R. Features of responding T cells in cancer and chronicinfection[J]. Curr Opin Immunol,2010,22(2):223-230.
[2] McIntire JJ,Umetsu SE,Akbari O,et al.Identification of Tapr (an airwayhyperreactivity rgulatory locus) and the linked TIM genefamily[J].NatImmunol,2001,2(12):1109-1116.
[3] Monney L.Th1-specific cell surfaceprotein TIM-3regulates macrophageactivationand severity of an autoimmune disease[J].Nature,2002,415:536-541.
[4] Nakae S,Iikura M,Suto H.et al.TIM-1andTIM-3enhancement of Th2cytokineproduction by mastcells[J].Blood,2007,110:2565-2568.
[5] Cua DJ,Sherloc kJ, Chen Y,Murphy CA.et al. Interleukin-23rather thaninterleukin-12is the critical cytokine for autoimmune inflammation of thebrain[J].Nature,2003,421:744-748.
[6] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expressed on innate immunecells[J].Science,2007,318:1141-1143.
[7] Wang F,He W,Zhou H,.et al.The TIM-3ligand galectin-9negatively regulatesCD8+alloreactive T cell and prolongs survival of skin graft[J]. CellImmunol.2007,250:68-74.
[8] Zhu C,Anderson AC,Schubart A,et al.The TIM-3ligand galectin-9negativelyregulates T helper type1immunity[J]. NatImmunol,2005,6(12):1245-1252.
[9] Sanchez-Fueyo A,Tian J, Picarella D,et al. TIM-3inhibits T helpertype1-mediated auto-and Alloimmune responses and promotes immuno-logicaltolerance[J]. Nat Immunol,2003,4(11):1093-1101.
[10] Sabatos CA,Chakravarti S,Cha E.et al.Interaction of TIM-3and TIM-3ligandregulates T helper type1responses and induction of peripheral tolerance[J]. NatImmunol,2003,4(11):1102-1110.
[11] Sehrawat S,Suryawanshi A,Hirashima M,et al.Role of TIM-3/galectin-9inhibitory interaction in viral-induced immunopathology: shifting the balance towardregulators[J]. J Immunol,2009,182(5):3191-3201.
[12] Anderson AC,Anderson DE.TIM-3in autoimmunity[J].Curr OpinImmunol,2006,18(6):665-669.
[13] Dardalhon V,Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11b+Ly-6G+myeloidcells[J]. J Immunol.2010,185(3):1383-1392.
[14] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expresse doninnate immunecells[J].Science,2007,318(5853):1141-1143.
[15] Wu FH,Yuan Y,Li D,et al.Endothelial cell-expressed TIM-3facilitatesmetastasis of melanoma cells by activating he NF-kappaB pathway[J].Oncol Rep,2010,24(3):693-699.
[16] Wiener Z,Kohalmi B,Pocza P,et al.TIM-3is expressed in melanoma cells andis upregulated in TGF-beta stimulated mastcells[J].InvestDermatol,2007,127(4):906-914.
[17] Huang X,Bai X,Cao Y,et al.Lymphoma endothelium preferentially expressesTIM-3and facilitates the progression of lymphoma by mediating immune evasion[J]. JExp Med,2010,207(3):505-520.
[18]. Zajac AJ,Blattman JN,Murali-Krishna K,et al. Viral immune evasion due topersistence of activated T cells without effector function [J]. J Exp Med1998,188:2205-2213.
[19]. Wherry EJ。T cell exhaustion[J]. Nat Immunol2011,12:492-499.
[20]. Sakuishi K, Apetoh L,Sullivan JM,et al. Targeting TIM-3PD-1pathwaysto reverse T cell exhaustion and restore anti-tumor immunity[J].J Exp Med2010,207:2187-2194.
[21] Zhou Q, Munger ME, Veenstra RG,et al.Coexpression of TIM-3and PD-1identifies a CD8T-cell exhaustion phenotype in mice with disseminated acutemyelogenous leukemia[J]. Blood2011,117:4501-4510.
[22] giow SF, von Scheidt B, Akiba H,et al.Anti-TIM3antibody promotes T cellIFN-γ-mediated anti-tumor immunity and suppresses established tumors [J].Cancer Res2011,71:6567-6571.
[23] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators ofthe immune system.Nat Rev Immunol.2009,9:162-74.
[24] Yang L, DeBusk LM, Fukuda K,et al. Expansion of myeloid immunesuppressor GrCD11b cells in tumor-bearing host directly promotes tumorangiogenesis.Cancer Cell2004,6(4):409-21.
[25] Thakur A, Schalk D, Tomaszewski E,et al.Microenvironment generatedduring EGFR targeted killing of pancreatic tumor cells by ATC inhibitsmyeloid-derived suppressor cells through COX2and PGE2dependentpathway[J].2013,11(1):35.
[26] Macphail SE,Gibney CA,Brooks BM,et al.Nitric oxide regulation of humanperipheral blood mononuclear cells:Critical time dependence and selectivity forcytokine versus chemokine expression[J].J Immunol,2003,171(9):4809-4815.
[27] Corzo CA,Cotter MJ,Cheng P,et al.Mechanism regulating reactive oxygenspecies in tumor-induced myeloid-derived suppressor cells[J].JImmunl,2009,182(9）:5693-56701.
[28] Dardalhon V, Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11bLy-6G myeloid cells[J]. JImmunol2010,185:1383-1392.
[29] Nakayama M, Akiba H, Takeda K,et al.TIM-3mediates phagocytosis ofapoptotic cells and cross-presentation[J].Blood2009,113:3821-3830.
[30] Huang X, Bai X, Cao Y, et al. Lymphoma endothelium preferentiallyexpresses TIM-3and facilitates the progression of lymphoma by mediating immuneevasion[J]. J Exp Med2010,207:505-520.
[31] Gao X, Zhu Y, Li G, et al.TIM-3Expression Characterizes Regulatory T Cellsin Tumor Tissues and Is Associated with Lung Cancer Progression. PLoS ONE7(2):e30676.
[32] Sui L, ZhangW, Chen Y, et al. Human membrane protein TIM23facilitateshepatitis Avirus entry into target cell [J]. Int J Mol Med,2006,17(6):109321099.
[33] Mariat C, Sanchez2Fueyo A, Alexopoulos SP, et al. Regulation of T celldependent immune responses by TIM family members [J]. Philos Trans R Soc Lond BBiol Sci,2005,360(1461):168121685.
[34] Fallarino F，Grohmann U，You S，et al.The combined effects of tryptophanstarvation and tryptophan catabolites down-regulate T cell receptor zetachain andinduce a regulatory phenotype in naive T cells[J].J Immunol，2006;176(11):6752-6761.
[1] Monney L.Th1-specific cell surfaceprotein TIM-3regulates macrophageactivationand severity of an autoimmune disease[J].Nature,2002,415:536-541.
[2] Nakae S,Iikura M,Suto H.et al.TIM-1andTIM-3enhancement of Th2cytokineproduction by mastcells[J].Blood,2007,110:2565-2568.
[3] Cua DJ,Sherloc kJ, Chen Y,Murphy CA.et al. Interleukin-23rather thaninterleukin-12is the critical cytokine for autoimmune inflammation of thebrain[J].Nature,2003,421:744-748.
[4] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expressed on innate immunecells[J].Science,2007,318:1141-1143.
[5] Wang F,He W,Zhou H,.et al.The TIM-3ligand galectin-9negatively regulatesCD8+alloreactive T cell and prolongs survival of skin graft[J]. CellImmunol.2007,250:68-74.
[6]Dardalhon V,Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulationof Th1immunity through promotion of CD11b+Ly-6G+myeloid cells[J]. JImmunol.2010,185(3):1383-1392.
[2] McIntire JJ,Umetsu SE,Akbari O,et al.Identification of Tapr (an airwayhyperreactivity rgulatory locus) and the linked TIM genefamily[J].NatImmunol,2001,2(12):1109-1116.
[3] Monney L.Th1-specific cell surfaceprotein TIM-3regulates macrophageactivationand severity of an autoimmune disease[J].Nature,2002,415:536-541.
[4] Nakae S,Iikura M,Suto H.et al.TIM-1andTIM-3enhancement of Th2cytokineproduction by mastcells[J].Blood,2007,110:2565-2568.
[5] Cua DJ,Sherloc kJ, Chen Y,Murphy CA.et al. Interleukin-23rather thaninterleukin-12is the critical cytokine for autoimmune inflammation of thebrain[J].Nature,2003,421:744-748.
[6] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expressed on innate immunecells[J].Science,2007,318:1141-1143.
[7] Wang F,He W,Zhou H,.et al.The TIM-3ligand galectin-9negatively regulatesCD8+alloreactive T cell and prolongs survival of skin graft[J]. CellImmunol.2007,250:68-74.
[8] Zhu C,Anderson AC,Schubart A,et al.The TIM-3ligand galectin-9negativelyregulates T helper type1immunity[J]. NatImmunol,2005,6(12):1245-1252.
[9] Sanchez-Fueyo A,Tian J, Picarella D,et al. TIM-3inhibits T helpertype1-mediated auto-and Alloimmune responses and promotes immuno-logicaltolerance[J]. Nat Immunol,2003,4(11):1093-1101.
[10] Sabatos CA,Chakravarti S,Cha E.et al.Interaction of TIM-3and TIM-3ligandregulates T helper type1responses and induction of peripheral tolerance[J]. NatImmunol,2003,4(11):1102-1110.
[11] Sehrawat S,Suryawanshi A,Hirashima M,et al.Role of TIM-3/galectin-9inhibitory interaction in viral-induced immunopathology: shifting the balance towardregulators[J]. J Immunol,2009,182(5):3191-3201.
[12] Anderson AC,Anderson DE.TIM-3in autoimmunity[J].Curr OpinImmunol,2006,18(6):665-669.
[13] Dardalhon V,Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11b+Ly-6G+myeloidcells[J]. J Immunol.2010,185(3):1383-1392.
[14] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expresse doninnate immunecells[J].Science,2007,318(5853):1141-1143.
[15] Wu FH,Yuan Y,Li D,et al.Endothelial cell-expressed TIM-3facilitatesmetastasis of melanoma cells by activating he NF-kappaB pathway[J].Oncol Rep,2010,24(3):693-699.
[16] Wiener Z,Kohalmi B,Pocza P,et al.TIM-3is expressed in melanoma cells andis upregulated in TGF-beta stimulated mastcells[J].InvestDermatol,2007,127(4):906-914.
[17] Huang X,Bai X,Cao Y,et al.Lymphoma endothelium preferentially expressesTIM-3and facilitates the progression of lymphoma by mediating immune evasion[J]. JExp Med,2010,207(3):505-520.
[18] Zajac AJ,Blattman JN,Murali-Krishna K,et al. Viral immune evasion due topersistence of activated T cells without effector function [J]. J Exp Med1998,188:2205-2213.
[19]. Wherry EJ.T cell exhaustion[J]. Nat Immunol2011,12:492-499.
[20]. Sakuishi K, Apetoh L,Sullivan JM,et al. Targeting TIM-3PD-1pathwaysto reverse T cell exhaustion and restore anti-tumor immunity[J].J Exp Med2010,207:2187-2194.
[21]. Zhou Q, Munger ME, Veenstra RG,et al.Coexpression of TIM-3and PD-1identifies a CD8T-cell exhaustion phenotype in mice with disseminated acutemyelogenous leukemia[J]. Blood2011,117:4501-4510.
[22] Sabatos C A.et al. Interacti on of TIM-3and TIM-3ligand regulates Thelper type1respones and induction of peripheral tolerance[J].Nat Immunol2010,4:1102–1110.
[23] McMahan R.H. et al.TIM-3expression on PD-1+HCV-specific humanCTLs is associated with viral persistence and its blockade restores hepatocyt e-directedin vitro cytotoxicit y[J]. Clin Invest2013,120:4546–4557.
[24] Takamura S,et al.Premature terminal exhaustion of Friend virus-specificeffector CD8+T cells by rapid induction of multipleinhibitory receptors[J]. J Immunol2010,184:4696–4707.
[25] giow SF, von Scheidt B, Akiba H,et al.Anti-TIM3antibody promotes T cellIFN-γ-mediated anti-tumor immunity and suppresses established tumors [J].Cancer Res2011,71:6567-6571.
[26] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators ofthe immune system.Nat Rev Immunol.2009,9:162-74.
[27] Yang L, DeBusk LM, Fukuda K,et al. Expansion of myeloid immunesuppressor GrCD11b cells in tumor-bearing host directly promotes tumorangiogenesis.Cancer Cell2004,6(4):409-21.
[28] Thakur A, Schalk D, Tomaszewski E,et al.Microenvironment generatedduring EGFR targeted killing of pancreatic tumor cells by ATC inhibitsmyeloid-derived suppressor cells through COX2and PGE2dependentpathway[J].2013,11(1):35.
[29] Macphail SE,Gibney CA,Brooks BM,et al.Nitric oxide regulation of humanperipheral blood mononuclear cells:Critical time dependence and selectivity forcytokine versus chemokine expression[J].J Immunol,2003,171(9):4809-4815.
[30] Corzo CA,Cotter MJ,Cheng P,et al.Mechanism regulating reactive oxygenspecies in tumor-induced myeloid-derived suppressor cells[J].JImmunl,2009,182(9）:5693-56701.
[31] Dardalhon V, Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11bLy-6G myeloid cells[J]. JImmunol,2010,185:1383-1392.
[32] Nakayama M, Akiba H, Takeda K,et al.TIM-3mediates phagocytosis ofapoptotic cells and cross-presentation[J].Blood,2009,113:3821-3830.
[33] Huang X, Bai X, Cao Y, et al. Lymphoma endothelium preferentiallyexpresses TIM-3and facilitates the progression of lymphoma by mediating immuneevasion[J]. J Exp Med,2010,207:505-520.
[34] Chiba S, Baghdadi M, Akiba H,et al.Tumor-infiltrating DCs suppress nucleicacid-mediated innate immune responses through interactions between the receptorTIM-3and the alarmin HMGB1[J].Nat Immunol,2012;13(9):832-842.
[35] Sui L, ZhangW, Chen Y, et al. Human membrane protein TIM-3facilitateshepatitis Avirus entry into target cell [J]. Int J Mol Med,2006,17(6):109321099.
[36] Mariat C, Sanchez2Fueyo A, Alexopoulos SP, et al. Regulation of T celldependent immune responses by TIM family members [J]. Philos Trans R Soc Lond BBiol Sci,2005,360(1461):168121685.
[37] Fallarino F，Grohmann U，You S，et al.The combined effects of tryptophanstarvation and tryptophan catabolites down-regulate T cell receptor zetachain andinduce a regulatory phenotype in naive T cells[J].J Immunol，2006;176(11):6752-6761.
[1] Monney L.Th1-specific cell surfaceprotein TIM-3regulates macrophageactivationand severity of an autoimmune disease[J].Nature,2002,415:536-541.
[2] Nakae S,Iikura M,Suto H.et al.TIM-1andTIM-3enhancement of Th2cytokineproduction by mastcells[J].Blood,2007,110:2565-2568.
[3] Cua DJ,Sherloc kJ, Chen Y,Murphy CA.et al. Interleukin-23rather thaninterleukin-12is the critical cytokine for autoimmune inflammation of thebrain[J].Nature,2003,421:744-748.
[4] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expressed on innate immunecells[J].Science,2007,318:1141-1143.
[5] Wang F,He W,Zhou H,.et al.The TIM-3ligand galectin-9negatively regulatesCD8+alloreactive T cell and prolongs survival of skin graft[J]. CellImmunol.2007,250:68-74.
[6] Dardalhon V,Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11b+Ly-6G+myeloidcells[J]. J Immunol.2010,185(3):1383-1392.
[7] Sui L, ZhangW, Chen Y, et al. Human membrane protein TIM23facilitateshepatitis Avirus entry into target cell [J]. Int J Mol Med,2006,17(6):109321099.
[8] Mariat C, Sanchez2Fueyo A, Alexopoulos SP, et al. Regulation of T celldependent immune responses by TIM family members [J]. Philos Trans R Soc Lond BBiol Sci,2005,360(1461):168121685.
[9] Ji XJ, Ma CJ, Wang JM,et al. HCV-infected hepatocytes drive CD4+CD25+Foxp3+regulatory T-cell development through the Tim-3/Gal-9pathway[J].Eur JImmunol,2013;43(2):458-467.
[10] Seki M, Oomizu S. Galectin-9suppresses the generation of Th17, promotesthe induction of regulatory T cells, and regulates experimental autoimmunearthritis[J].Clin Immunol,2008;127(1):78-88.
[11] Yan J, Zhang Y, Zhang JP,et al. Tim-3expression defines regulatory T cells inhuman tumors[J].PLoS One,2013;8(3):e58006.
[12] Sakuishi K, Apetoh L,Sullivan JM,et al.Targeting TIM-3PD-1pathways toreverse T cell exhaustion and restore anti-tumor immunity[J].J Exp Med2010,207:2187-2194.
[13] Zhou Q, Munger ME, Veenstra RG,et al.Coexpression of TIM-3and PD-1identifies a CD8T-cell exhaustion phenotype in mice with disseminated acutemyelogenous leukemia[J]. Blood2011,117:4501-4510.
[14] Dardalhon V, Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11bLy-6G myeloid cells[J]. JImmunol2010,185:1383-1392.
[15] Ghansah T. A novel strategy for modulation of MDSC to enhance cancerimmunotherapy[J].Oncoimmunology,2012,1(6):984-985.
[16] Yu J, Du W, Yan F,et al.Myeloid-Derived Suppressor Cells SuppressAntitumor Immune Responses through IDO Expression and Correlate with LymphNode Metastasis in Patients with Breast Cancer[J].J Immunol.,2013,190(7):3783-3797.
[1] Kim PS, Ahmed R. Features of responding T cells in cancer and chronicinfection[J]. Curr Opin Immunol,2010,22(2):223-230.
[2] McIntire JJ,Umetsu SE,Akbari O,et al.Identification of Tapr (an airwayhyperreactivity rgulatory locus) and the linked TIM genefamily[J].NatImmunol,2001,2(12):1109-1116.
[3] Monney L.Th1-specific cell surfaceprotein TIM-3regulates macrophageactivationand severity of an autoimmune disease[J].Nature,2002,415:536-541.
[4] Nakae S,Iikura M,Suto H.et al.TIM-1andTIM-3enhancement of Th2cytokineproduction by mastcells[J].Blood,2007,110:2565-2568.
[5] Cua DJ,Sherloc kJ, Chen Y,Murphy CA.et al. Interleukin-23rather thaninterleukin-12is the critical cytokine for autoimmune inflammation of thebrain[J].Nature,2003,421:744-748.
[6] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expressed on innate immunecells[J].Science,2007,318:1141-1143.
[7] Wang F,He W,Zhou H,.et al.The TIM-3ligand galectin-9negatively regulatesCD8+alloreactive T cell and prolongs survival of skin graft[J]. CellImmunol.2007,250:68-74.
[8] Zhu C,Anderson AC,Schubart A,et al.The TIM-3ligand galectin-9negativelyregulates T helper type1immunity[J]. NatImmunol,2005,6(12):1245-1252.
[9] Sanchez-Fueyo A,Tian J, Picarella D,et al. TIM-3inhibits T helpertype1-mediated auto-and Alloimmune responses and promotes immuno-logicaltolerance[J]. Nat Immunol,2003,4(11):1093-1101.
[10] Sabatos CA,Chakravarti S,Cha E.et al.Interaction of TIM-3and TIM-3ligandregulates T helper type1responses and induction of peripheral tolerance[J]. NatImmunol,2003,4(11):1102-1110.
[11] Sehrawat S,Suryawanshi A,Hirashima M,et al.Role of TIM-3/galectin-9inhibitory interaction in viral-induced immunopathology: shifting the balance towardregulators[J]. J Immunol,2009,182(5):3191-3201.
[12] Anderson AC,Anderson DE.TIM-3in autoimmunity[J].Curr OpinImmunol,2006,18(6):665-669.
[13] Dardalhon V,Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11b+Ly-6G+myeloidcells[J]. J Immunol.2010,185(3):1383-1392.
[14] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expresse doninnate immunecells[J].Science,2007,318(5853):1141-1143.
[15] Wu FH,Yuan Y,Li D,et al.Endothelial cell-expressed TIM-3facilitatesmetastasis of melanoma cells by activating he NF-kappaB pathway[J].Oncol Rep,2010,24(3):693-699.
[16] Wiener Z,Kohalmi B,Pocza P,et al.TIM-3is expressed in melanoma cells andis upregulated in TGF-beta stimulated mastcells[J].InvestDermatol,2007,127(4):906-914.
[17] Huang X,Bai X,Cao Y,et al.Lymphoma endothelium preferentially expressesTIM-3and facilitates the progression of lymphoma by mediating immune evasion[J]. JExp Med,2010,207(3):505-520.
[18]. Zajac AJ,Blattman JN,Murali-Krishna K,et al. Viral immune evasion due topersistence of activated T cells without effector function [J]. J Exp Med1998,188:2205-2213.
[19]. Wherry EJ。T cell exhaustion[J]. Nat Immunol2011,12:492-499.
[20]. Sakuishi K, Apetoh L,Sullivan JM,et al. Targeting TIM-3PD-1pathwaysto reverse T cell exhaustion and restore anti-tumor immunity[J].J Exp Med2010,207:2187-2194.
[21] Zhou Q, Munger ME, Veenstra RG,et al.Coexpression of TIM-3and PD-1identifies a CD8T-cell exhaustion phenotype in mice with disseminated acutemyelogenous leukemia[J]. Blood2011,117:4501-4510.
[22] giow SF, von Scheidt B, Akiba H,et al.Anti-TIM3antibody promotes T cellIFN-γ-mediated anti-tumor immunity and suppresses established tumors [J].Cancer Res2011,71:6567-6571.
[23] Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators ofthe immune system.Nat Rev Immunol.2009,9:162-74.
[24] Yang L, DeBusk LM, Fukuda K,et al. Expansion of myeloid immunesuppressor GrCD11b cells in tumor-bearing host directly promotes tumorangiogenesis.Cancer Cell2004,6(4):409-21.
[25] Thakur A, Schalk D, Tomaszewski E,et al.Microenvironment generatedduring EGFR targeted killing of pancreatic tumor cells by ATC inhibitsmyeloid-derived suppressor cells through COX2and PGE2dependentpathway[J].2013,11(1):35.
[26] Macphail SE,Gibney CA,Brooks BM,et al.Nitric oxide regulation of humanperipheral blood mononuclear cells:Critical time dependence and selectivity forcytokine versus chemokine expression[J].J Immunol,2003,171(9):4809-4815.
[27] Corzo CA,Cotter MJ,Cheng P,et al.Mechanism regulating reactive oxygenspecies in tumor-induced myeloid-derived suppressor cells[J].JImmunl,2009,182(9）:5693-56701.
[28] Dardalhon V, Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulation of Th1immunity through promotion of CD11bLy-6G myeloid cells[J]. JImmunol2010,185:1383-1392.
[29] Nakayama M, Akiba H, Takeda K,et al.TIM-3mediates phagocytosis ofapoptotic cells and cross-presentation[J].Blood2009,113:3821-3830.
[30] Huang X, Bai X, Cao Y, et al. Lymphoma endothelium preferentiallyexpresses TIM-3and facilitates the progression of lymphoma by mediating immuneevasion[J]. J Exp Med2010,207:505-520.
[31] Gao X, Zhu Y, Li G, et al.TIM-3Expression Characterizes Regulatory T Cellsin Tumor Tissues and Is Associated with Lung Cancer Progression. PLoS ONE7(2):e30676.
[32] Sui L, ZhangW, Chen Y, et al. Human membrane protein TIM23facilitateshepatitis Avirus entry into target cell [J]. Int J Mol Med,2006,17(6):109321099.
[33] Mariat C, Sanchez2Fueyo A, Alexopoulos SP, et al. Regulation of T celldependent immune responses by TIM family members [J]. Philos Trans R Soc Lond BBiol Sci,2005,360(1461):168121685.
[34] Fallarino F，Grohmann U，You S，et al.The combined effects of tryptophanstarvation and tryptophan catabolites down-regulate T cell receptor zetachain andinduce a regulatory phenotype in naive T cells[J].J Immunol，2006;176(11):6752-6761.
[1] Monney L.Th1-specific cell surfaceprotein TIM-3regulates macrophageactivationand severity of an autoimmune disease[J].Nature,2002,415:536-541.
[2] Nakae S,Iikura M,Suto H.et al.TIM-1andTIM-3enhancement of Th2cytokineproduction by mastcells[J].Blood,2007,110:2565-2568.
[3] Cua DJ,Sherloc kJ, Chen Y,Murphy CA.et al. Interleukin-23rather thaninterleukin-12is the critical cytokine for autoimmune inflammation of thebrain[J].Nature,2003,421:744-748.
[4] Anderson AC,Anderson DE,Bregoli L,et al.Promotion of tissue inflammationby the immune receptor TIM-3expressed on innate immunecells[J].Science,2007,318:1141-1143.
[5] Wang F,He W,Zhou H,.et al.The TIM-3ligand galectin-9negatively regulatesCD8+alloreactive T cell and prolongs survival of skin graft[J]. CellImmunol.2007,250:68-74.
[6]Dardalhon V,Anderson AC,Karman J,et al.TIM-3/galectin-9pathway:regulationof Th1immunity through promotion of CD11b+Ly-6G+myeloid cells[J]. JImmunol.2010,185(3):1383-1392.