Foxp3+ Treg细胞与胃癌的研究进展

调节性T细胞(Treg)是重要的免疫调节功能细胞,叉头状p3因子(Foxp3)对Treg细胞的发育和功能调节至关重要。通常认为Foxp3+Treg细胞通过抑制效应T细胞功能从而削弱机体对肿瘤细胞的免疫反应,对肿瘤的发生发展有着密切的联系。这些细胞主要是肿瘤浸润性淋巴细胞(TIL)中的Foxp3+Treg细胞,其聚集在癌周的具体机制仍不清楚。然而,亦有认为Foxp3+Treg细胞可抑制肿瘤生长,Foxp3高表达与疾病的良好预后有关。笔者通过文献复习,分析结论相左的原因可能与胃癌类型、Foxp3检测抗体、Foxp3+Treg细胞亚型有关。因此,鉴定出具有稳定免疫抑制功能的Foxp3+Treg细胞亚型,分析各亚型与各类型胃癌之间的关系,才能得出更可靠的数据。     

胃肠间质瘤的外科及靶向治疗策略

众所周知,伊马替尼等靶向药物改变了胃肠间质瘤（GIST）病人的治疗策略。但目前伊马替尼等的应用已从单纯药物治疗模式向与外科治疗联合应用的模式转变。PET?CT显像结果与临床症状缓解相一致,可早期评价GIST病人的疗效。动态增强超声造影已成为GIST靶向药物治疗疗效评价新的功能成像方法。对于高危的GIST病人,术后应采用伊马替尼辅助治疗1~2年。新辅助治疗在GIST中的应用已被广泛接受。目前认为对于伊马替尼耐药的病例,应用舒尼替尼治疗是安全可接受的。     

对复发转移性胃肠间质瘤手术还是不手术

复发转移性胃肠间质瘤（GIST）的处理是目前临床治疗的一大难题。国际上一些大型临床试验显示．伊马替尼治疗可显著改善复发转移GIST患者的生存期。而手术联合伊马替尼已成为转移GIST的理想治疗方法。然而．两者如何联合应用尚存在争议。伊马替尼可能影响凝血机制．因此,建议术前1周停药。细胞减灭术在复发转移性GIST中有一定的临床疗效,可与靶向药物联合应用。而复发转移GIST的临床试验尚需进一步评价。     

伊马替尼耐药晚期胃肠间质瘤治疗策略

胃肠间质瘤（GIST）是消化道最常见的间叶组织来源肿瘤。目前伊马替尼是转移或不可切除GIST的标准一线治疗药物。近10年随着伊马替尼进入GIST的治疗领域,以往不可治愈GIST病人的预后得到明显改善。然而,多数伊马替尼初始治疗有效的晚期GIST,会在2～3年内发展成伊马替尼继发耐药,原因可能与肿瘤中存在继发c-kit基因突变的多细胞克隆有关。舒尼替尼和新近的瑞格非尼均已获美国食品药品监督管理局（FDA）批准分别用于伊马替尼治疗失败的GIST二线和三线治疗,从而拓展了伊马替尼耐药GIST的治疗选择。对于酪氨酸激酶抑制剂治疗基础上出现局部进展的转移GIST,减瘤手术可使病人获益。对于伴发急性肠梗阻、穿孔或出血的晚期GIST,手术可减轻病人症状。     

对伊马替尼继发耐药的晚期胃肠道间质瘤治疗策略探讨

目的 探讨对伊马替尼继发耐药的复发和转移的晚期胃肠道间质瘤（gastrointestinal stromal tumors, GIST）的治疗策略。方法 回顾性分析复旦大学附属中山医院2000—2009年对伊马替尼继发耐药的复发和转移的晚期8例GIST病人的临床资料。结果 所有病人均行手术治疗,完整切除原发肿瘤后,肿瘤复发和（或）转移,口服伊马替尼治疗产生继发耐药,采取手术切除复发和转移灶（特别是耐药病灶）联合伊马替尼等靶向治疗为主的综合治疗模式,均获得较好的治疗效果。1例死亡,存活96个月;其余7例仍存活,目前存活时间65~145个月,平均98.6个月。结论 伊马替尼继发耐药的复发和转移的晚期GIST,选择手术联合酪氨酸激酶抑制剂靶向治疗为主的多学科综合治疗模式,参考肿瘤的基因状态,采取个体化治疗,可取得较好的疗效。     

胃肠间质瘤分子靶向治疗耐药机制及对策

胃肠间质瘤（GIST）是一种特殊类型的间叶源性肿瘤．伊马替尼和舒尼替尼等小分子靶向药物是除手术外治疗GIST有效治疗方法。然而部分肿瘤对伊马替尼和（或）舒尼替尼存在原发性或继发性耐药。基因突变类型的差异以及继发基因突变是导致耐药的主要原因。临床上一旦出现肿瘤耐药．应根据耐药种类、耐药原因以及肿瘤具体情况．制订合理而个体化的治疗策略,提高治疗效果,改善生存质量。     

胃肠间质瘤靶向治疗耐药的分子机制及治疗策略

胃肠间质瘤（GIST）是胃肠道最常见的间叶源性肿瘤。功能获得性突变所致的c-kit或PDGFRA受体酪氨酸激酶异常活化是大多数GIST发病的关键因素。伊马替尼及舒尼替尼等分子靶向药物可特异性抑制酪氨酸激酶受体活化．其作为治疗晚期GIST及高危GIST术后辅助治疗的一线治疗地位已经得到广泛认可,并成为了实体肿瘤分子靶向治疗的经典模型。但同时以上药物的耐药问题一直是临床治疗中的棘手难题和研究热点。许多因素与发生伊马替尼或舒尼替尼耐药有关,其中．KIT／PDGFRA的基因突变是决定耐药与否的主要原因。此外,可能还涉及基因扩增、杂合性丢失和近膜热点区域之外的旁路激活及药物血浆浓度等原因。对于出现肿瘤耐药的患者,应根据不同的耐药原因,采取相应的个体化治疗策略,以期提高治疗效果,改善患者生活质量。     

胃肠道间质瘤的分子靶向治疗

分子靶向药物的出现,改变了胃肠道间质瘤(GIST)的治疗模式.伊马替尼400 mg/d被推荐为转移性GIST的标准一线治疗方案.伊马替尼标准剂量治疗失败后,增加伊马替尼剂量或换用舒尼替尼治疗可进一步延长患者生存时间,同时新的分子靶向药物显示出了治疗GIST的潜在活性.GIST完整切除术后,伊马替尼辅助治疗可改善中高度复发风险患者的无复发生存率.伊马替尼术前治疗可提高手术切除率,但是否使患者生存获益尚未得到最终证实.c-kit和(或)血小板源性生长因子受体α(PDGFRα)基因突变可以预测伊马替尼与舒尼替尼的疗效,同时亦有助于辅助治疗获益人群的筛选.     

伊马替尼治疗胃肠间质瘤的继发性耐药机制

胃肠间质瘤（gastrointestinal stromal tumors,GIST）是胃肠道最常见的间叶源性肿瘤,对传统放疗或化疗几乎无效。伊马替尼作为进展或不可切除GIST治疗的一线药物,有较好的疗效。但研究显示,GIST患者对伊马替尼存在广泛的继发耐药现象。探索伊马替尼的继发耐药机制,是目前肿瘤分子生物学研究的热点．具有重要的临床意义。     

胃肠间质瘤免疫疗法及新策略的研究进展

胃肠道间质瘤（GIST）是源自Cajal间质细胞的软组织肿瘤,是胃肠道肉瘤的一种常见类型。靶向药物的发现大大提高了GIST的生存率,而伊马替尼作为靶向药物,已经成为GIST的一线治疗药物。然而,最近研究发现,大多数患者已经对伊马替尼产生了耐药性。最新的研究表明,免疫疗法,包括基于免疫检查点抑制剂和伊马替尼联合疗法、细胞因子、抗KIT抗体、双特异性单克隆抗体疗法和其他新型策略,对治疗胃肠道间质瘤也是有效的。在本综述中,将讨论免疫疗法和其他新策略在治疗胃肠道间质瘤中的作用。     

Foxp3 is critical for human natural CD4+CD25+ regulatory T cells to suppress alloimmune response

Naturally occurring CD4+CD25+ regulatory T cells (nTregs) that express high level of Foxp3 actively suppress pathological and physiological immune responses, contributing to the maintenance of immunological self-tolerance and immune homeostasis. Although Foxp3 is required for nTreg development and appears to be necessary for mature murine Treg function, the precise role of Foxp3 in regulating natural human Treg function in alloimmune response is unclear. In this study, we used siRNA-mediated gene silencing to knockdown Foxp3 expression in natural human Tregs and investigated the importance of Foxp3 in maintaining human nTreg suppressive function. We showed that Foxp3 knockdown resulted in impaired phenotype and nonresponsiveness, downregulated expression of function molecules, and reduced production of suppressive cytokines in nTregs. These changes correlated with diminished nTreg activity in suppressing proliferation of effector CD4+CD25- T cells, their cytotoxicity against allogeneic target cells and production of effector cytokines in response to allogeneic stimulation. Thus, this study shows that ongoing Foxp3 expression is required for natural human Tregs to maintain their phenotype and suppressive function in the alloimmune response.     

胃肠间质瘤治疗进展

胃肠间质瘤（GIST）是胃肠道最常见的间叶来源肿瘤。大部分患者存在c-kit或PDGFRa基因突变。手术根治性切除是治疗胃肠间质瘤的基石,但是术后复发率较高。近年来,以伊马替尼为代表的靶向治疗大大提高了GIST治疗效果。对于手术可以切除的患者,手术切除联合新辅助或辅助治疗改善了高危患者的预后：对于手术不可切除的患者,靶向治疗也有效地抑制、延缓了病情的进展。     

TGF-β Induces Foxp3 + T-Regulatory Cells from CD4 + CD25 − Precursors

CD4 + CD25 + regulatory T cells (Tregs) are potent suppressors, playing important roles in autoimmunity and transplantation tolerance. Understanding the signals necessary for the generation and expansion of Tregs is important for clinical cellular therapy, but only limited progress has been made. Recent reports suggest a role for TGF-beta in the generation of Tregs from CD4 + CD25 - precursors, but the mechanism remains unknown. Here, we demonstrate that TGF-beta2 triggers Foxp3 expression in CD4 + CD25 - precursors, and these Foxp3 + cells act like conventional Tregs. The generation of Foxp3 + Tregs requires stimulation of the T-cell receptor, the IL-2R and the TGF-beta receptor. More importantly, strong costimulation through CD28 prevents Foxp3 expression and suppressive function in an IL-4-dependent manner. Furthermore, TGF-beta-driven Tregs inhibit innate inflammatory responses to syngeneic transplanted pancreatic islets and enhance islet transplant survival. Thus, TGF-beta is a key regulator of the signaling pathways that initiate and maintain Foxp3 expression and suppressive function in CD4 + CD25 - precursors. TGF-beta and signaling through TGF-beta receptor, CD28 costimulation and IL-4 may be key components for the manipulation of Treg. The de novo generation of Foxp3 + cells from CD4 + cells has the potential to be used for treatment of autoimmune diseases and induction of transplant tolerance.     

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??Surgery management for patients with gastrointestinal stromal tumor in the era of targeted therapy YE Ying-jiang, WANG Shan. Department of Gastrointestinal Surgery, Peking University People’s Hospital, Beijing 100044, China
Corresponding author: WANG Shan, E-mail: shwang60@263.net.
Abstract Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract. For long time, the only proven therapy was surgery. The use of imatinib for targeted therapy has marked a new era in treatment. The surgical management of GIST has rapidly changed in the era of targeted therapy, and gotten advances in surgical principle, surgical technique and time of surgery, based on evidence-based medicine. Multidisciplinary approaches included targeted treatment and surgical treatment are the future to successfully treat patients with GIST. Complete resection without tumor rupture is still gold standard of curative treatment for localized, resectable, primary disease. In advanced patients, imatinib has been the standard treatment. For patients with advanced GIST responsive to imatinib, combined surgical plus targeted therapy may be most effective and improve survival.     

Combined surgical and molecular therapy: the gastrointestinal stromal tumor model

OBJECTIVE: This review describes the pathologic and epidemiologic features of gastrointestinal stromal tumor (GIST) as well as the contemporary management of this tumor. The integration of surgery and treatment with targeted molecular agents in the treatment of GIST is highlighted. SUMMARY BACKGROUND DATA: GIST is the most common mesenchymal tumor of the gastrointestinal tract. Its cellular origin from the interstitial cell of Cajal and distinctness from smooth muscles tumors were only recently appreciated. The discovery of the centrality of KIT proto-oncogene mutations in the pathogenesis of this tumor, and the development of imatinib mesylate, a specific inhibitor of KIT tyrosine kinase function have revolutionized the treatment of GIST. METHODS: We conducted a review of the English literature on GIST. The pathology, epidemiology, diagnosis, and treatment of this tumor are summarized with particular emphasis on recent developments in the field. RESULTS: GIST is a rare tumor that usually arises from the stomach or small intestine. It is characterized by immunohistochemical staining for KIT. Treatment of primary localized tumors is surgical. The benefit of adjuvant treatment with the KIT tyrosine kinase inhibitor imatinib is the subject of investigation. The treatment of unresectable, recurrent, or metastatic GIST is primarily imatinib treatment. The integration of surgery or ablative modalities is often employed, particularly when all disease is amenable to gross resection or destruction, or when GIST becomes resistant to imatinib. Newer tyrosine kinase inhibitors, such as sunitinib are the subject of ongoing investigation. CONCLUSIONS: The treatment paradigm for GIST has required the integration of surgery and molecular therapy and this will likely serve as a paradigm for the treatment of other solid tumors as targeted agents are developed.     

1-甲基色氨酸对胰腺癌荷瘤鼠中调节性T细胞数量变化的影响

目的 观察1-甲基色氨酸(1-MT)对胰腺癌荷瘤鼠中调节性T细胞(Treg)数量变化的影响,比较树突状细胞(DC)疫苗与1-MT联合应用前后抗肿瘤作用的强弱.方法 建立小鼠胰腺癌模型;利用流式细胞术检测荷瘤鼠应用1-MT前后肿瘤组织周围引流淋巴结(TDLNs)及脾脏中CD4~+ CD25~+T细胞占CD4~+T比例;荧光定量聚合酶链反应(PCR)测量Foxp3在TDLNs及脾脏mRNA水平;利用肿瘤细胞裂解物冲击DC制备DC疫苗,并根据是否与1-MT联合应用分组(各组均为n=8);观测各组肿瘤体积的差异.结果 应用1-MT后,荷瘤鼠CD4~+ CD25~+ T细胞占CD~+T细胞的比例明显低于未应用组(TDLNs)分别为(16.01±2.21)%和(25.00±2.16)%(P<0.05);脾脏分别为(13.11±1.93)%和(22.14±2.33)%(P<0.05,P<0.01);应用1-MT组Foxp3 mRNA表达水平显著低于未应用组,应用1-MT组相对表达值:TDLNs0.947±0.216、脾细胞1.198±0.347,而未应用组分别为:1.927±0.256、1.798±0.237(P<0.05);1-MT+DC疫苗组肿瘤生长显著受到抑制,第36天肿瘤体积为(789.0±111.0)mm~3;显著小于DC疫苗组、1-MT组及对照组,肿瘤体积分别为:(1768.0±251.3)、(1854.0±192.1)、(1899.0±201.2)mm~3(P<0.01).结论 1-MT可以有效抑制胰腺癌荷瘤鼠癌组织周围引流淋巴结及脾脏CD4~+ CD25~+ Treg细胞的数量增加,从而增强DC疫苗抗肿瘤作用.     

CD8+T细胞和调节性T细胞在食管癌中表达及与预后的关系

目的 探讨食管癌组织中CD8+T细胞、Foxp3阳性调节性T细胞(regulatory T cells,Treg)表达及对预后的影响.方法 应用免疫组织化学SP法检测CD8、Foxp3在90例食管癌组织间质、癌巢中的表达,计数阳性细胞,分析阳性细胞数目与预后的关系.结果 间质中CD8+T细胞的数量与浸润深度、分化程度呈负相关(P<0.05);Foxp3+Treg细胞数量与淋巴结转移、病变长度呈正相关(P<0.05).本组病例3年总生存率66.67%(60/90).单因素生存分析显示,无论癌巢或间质中,CD8+T细胞计数高者的总体生存曲线优于计数低者,差异有统计学意义(P<0.05);roxp3+Treg细胞计数高者的累计生存情况较计数低者差(P<0.05).多因素分析显示,间质浸润的CD8+T、Foxp3+Treg细胞数量和病变长度是影响生存期的独立因素(P<0.05).结论 间质中浸润的CD8+T细胞数量、Foxp3+Treg细胞数量是影响食管癌患者预后的独立因素,Foxp3+Treg细胞数量增多预后不良,CD8+T细胞数量增多则预后良好.