本文選題：卵巢癌　切入點：調(diào)節(jié)性T細(xì)胞　出處：《天津醫(yī)科大學(xué)》2015年博士論文　論文類型：學(xué)位論文

【摘要】：目的作為常見婦科腫瘤之一,卵巢癌死亡率高,居婦科惡性腫瘤第一位。卵巢癌目前的治療方案是以手術(shù)為主,術(shù)后輔助化療、放療、生物治療等的綜合治療。由于70%左右的患者就診時已于晚期,綜合治療后的患者仍有80%~85%左右會于短期內(nèi)出現(xiàn)復(fù)發(fā)與轉(zhuǎn)移,嚴(yán)重影響到卵巢癌患者治療的療效與預(yù)后,威脅著患者的生命。因此,尋找新的輔助治療方法,提高或改善現(xiàn)有治療手段的效果,以期實現(xiàn)遏制腫瘤轉(zhuǎn)移和延緩腫瘤復(fù)發(fā)、提高生存率和改善生存質(zhì)量的目的。多方研究報道表明,以往多種腫瘤免疫治療方案效果不佳的原因可能與腫瘤免疫微環(huán)境相關(guān),現(xiàn)在的研究主要集中在有關(guān)腫瘤免疫抑制微環(huán)境中免疫抑制細(xì)胞及其相關(guān)細(xì)胞因子在腫瘤免疫治療中作用,這類研究希望能在不遠(yuǎn)的將來為腫瘤的治療帶來新的突破,也將為腫瘤免疫治療效果不佳的現(xiàn)狀提供新的解釋。本研究通過檢測卵巢癌外周血中CD33+HLA-DR-/low髓系來源抑制性細(xì)胞(myeloid-derived suppressor cells,MDSCs)、CD4+CD25+CD127-/low調(diào)節(jié)性T細(xì)胞(regulatory T cells,Tregs)的含量及卵巢癌患者血清中Th1、Th2類細(xì)胞因子的表達(dá),分析這些腫瘤免疫微環(huán)境中的重要組成因素在卵巢癌患者中的表達(dá)特點,進一步分析它們與卵巢癌各項臨床病理參數(shù)的關(guān)系,為深入揭示免疫抑制因素與卵巢癌進展及治療的關(guān)系提供依據(jù),為探索能夠全面控制腫瘤免疫抑制微環(huán)境的有效措施提供實驗基礎(chǔ)。方法選擇72例卵巢癌患者作為研究對象,30例健康人群作為對照組。采集清晨空腹外周血。應(yīng)用流式細(xì)胞術(shù)檢測外周血中CD33+HLA-DR-/low髓系來源抑制性細(xì)胞(myeloid-derived suppressor cells,MDSCs)和CD4+CD25+CD127-/low調(diào)節(jié)性T細(xì)胞(regulatory T cells,Tregs)的含量,分析二者在卵巢癌患者外周血中的表達(dá)特點,探討二者與卵巢癌患者年齡、腫瘤大小、病理類型、病理分級、臨床分期等各項臨床病理參數(shù)的關(guān)系,探討二者表達(dá)的相關(guān)性。應(yīng)用BD CBA流式液相多重蛋白定量技術(shù)檢測卵巢癌患者血清中Th1、Th2類細(xì)胞因子的表達(dá)及其與臨床病理參數(shù)的關(guān)系。結(jié)果1.卵巢癌患者外周血中MDSCs為一群CD33陽性而HLA-DR陰性表達(dá)或低表達(dá)的細(xì)胞,與健康對照組(0.762±0.214)%相比,卵巢癌患者外周血中CD33+HLA-DR-/lowMDSCs的表達(dá)比例明顯升高(3.391±1.931)%,差異有統(tǒng)計學(xué)意義(P0.01);其表達(dá)水平與卵巢癌患者的年齡、腫瘤大小、病理類型無關(guān)(P0.05),而與卵巢癌患者病理分級、臨床分期具有明顯聯(lián)系,差異具有統(tǒng)計學(xué)意義(P0.05);與術(shù)前比較,手術(shù)后外周血中CD33+HLA-DR-/low MDSCs的表達(dá)水平(2.019±1.034)%明顯降低,差異具有統(tǒng)計學(xué)意義(P0.05);2.卵巢癌患者外周血中Treg細(xì)胞為一群CD4和CD25雙陽性而CD127低表達(dá)的細(xì)胞,平均百分比(14.068±4.546)%,較健康對照組外周血中(5.051±1.170)%顯著增高,差異具有統(tǒng)計學(xué)意義(P0.01);Treg細(xì)胞的表達(dá)與卵巢癌患者的年齡、腫瘤大小、病理類型及腫瘤分化程度均無明顯的相關(guān)性(P0.05),而與卵巢癌患者的臨床分期密切相關(guān),具有顯著的統(tǒng)計學(xué)差異(P0.05);手術(shù)后外周血中CD4+CD25+CD127-/lowTregs的平均百分比為(12.243±4.213)%,較術(shù)前有所降低,差異具有統(tǒng)計學(xué)意義(P0.05);3.卵巢癌患者外周血中CD33+HLA-DR-/lowMDSCs的表達(dá)與CD4+CD25+CD127-/low Tregs的表達(dá)具有明顯的相關(guān)性(n=72,r=0.0563,P0.05);4.卵巢癌患者血清中的Thl類細(xì)胞因子IL-2,IFN-γ的水平明顯低于正常人(P0.01),而Th2類細(xì)胞因子IL-6、IL-10的水平顯著高于正常人(P0.01),IL-4,TNF的水平與健康人比較無顯著差異。且早期患者血清中IL-2,IFN-γ的水平明顯高于晚期患者,而IL-6、IL-10的表達(dá)水平則低于晚期患者。結(jié)論卵巢癌患者外周血中免疫抑制性細(xì)胞CD33+HLA-DR-/low MDSCs和CD4+CD25+CD127-/lowTregs含量較健康對照均明顯增高,二者的表達(dá)表現(xiàn)出明顯的相關(guān)性,且Thl類細(xì)胞因子的水平降低,Th2類細(xì)胞因子的水平增高,提示卵巢癌患者體內(nèi)免疫抑制狀態(tài)的形成,為尋找卵巢癌獨特的免疫調(diào)節(jié)機制以逆轉(zhuǎn)卵巢癌免疫缺陷、改善卵巢癌預(yù)后提供了有力的實驗依據(jù)和方法基礎(chǔ)。
[Abstract]:Objective as one of the most common gynecological tumors, ovarian cancer mortality is high, ranking first in gynecological malignant tumor. Treatment of ovarian cancer is surgery, adjuvant chemotherapy, postoperative radiotherapy, biological therapy and other comprehensive treatment. Since about 70% of the patients have been in the late stage, after the comprehensive treatment of patients is about 80%~85% there will be recurrence and metastasis in the short term, seriously affect the curative effect and prognosis of patients with ovarian cancer treatment, threatening the lives of patients. Therefore, looking for new adjuvant treatment, improve or improve the existing treatment effect, in order to achieve curb tumor metastasis and delay the tumor recurrence and improve survival rate and improve the quality of life. Objective. Many reports indicated that the possible reasons for treatment scheme for multiple tumor immune effect and tumor immune microenvironment, now the research mainly focuses on the related tumor immunity Inhibition in the microenvironment of immunosuppressive cells and related cytokines in tumor immunotherapy, this kind of hope in the near future for cancer therapy bring new breakthrough, will also provide a new explanation for the status of tumor immunotherapy effect. This study through the detection of ovarian cancer in peripheral blood CD33+HLA-DR-/low myeloid derived suppressor cells (myeloid-derived suppressor cells, MDSCs), CD4+CD25+CD127-/low regulatory T cells (regulatory T cells, Tregs) and the content of Th1 in serum of patients with ovarian cancer, the expression of Th2 cytokines and expression analysis of characteristics in patients with ovarian cancer in these important factors in the tumor microenvironment, further analysis their relationship with clinicopathological parameters in ovarian cancer, and provide the basis for further revealing the relationship between progress and treatment of immunosuppressive factors and ovarian cancer, to explore the can Comprehensive and effective measures to control the immunosuppressive microenvironment provide experimental basis. Methods 72 cases of ovarian cancer patients as the research object, as a control group of 30 healthy people. Collected fasting peripheral blood. Flow cytometry was used to detect peripheral blood CD33+HLA-DR-/low myeloid derived suppressor cells (myeloid-derived suppressor cells, MDSCs) and CD4+CD25+CD127-/low regulatory T cells (regulatory T cells, Tregs) content, expression of the characteristics of the two in patients with ovarian cancer in the peripheral blood of two patients, age, ovarian cancer and tumor size, pathological type, pathological grade, clinical stage and relationship between clinicopathological parameters, to investigate the correlation between the expression of two the application of BD CBA flow liquid multiple protein quantitative detection of serum Th1 in patients with ovarian cancer, expression of Th2 cytokines and its relationship with clinicopathological parameters. Results 1. Ovarian cancer patients peripheral blood MDSCs for a group of CD33 positive and HLA-DR negative expression or low expression of the cells, and the healthy control group (0.762 + 0.214)% compared to the ratio of CD33+HLA-DR-/lowMDSCs expression in peripheral blood of patients with ovarian cancer were significantly higher (3.391 + 1.931)%, the difference was statistically significant (P0.01); the the expression level of ovarian cancer and the patient's age, tumor size, pathological type, and independent (P0.05) classification and pathology of patients with ovarian cancer, the clinical stage is obviously, the difference was statistically significant (P0.05); compared with the preoperative, the expression level of CD33+HLA-DR-/low in peripheral blood of MDSCs after surgery (2.019 + 1.034)% was decreased, the difference was statistically significant (P0.05); 2. patients with ovarian cancer Treg cells in peripheral blood for a group of CD4 and CD25 double positive and low expression of CD127 cells, the average percentage (14.068 + 4.546)%, compared with the healthy control group in peripheral blood (5.051 + 1.170)% Significantly, the difference was statistically significant (P0.01); Treg cells expressed in patients with ovarian cancer and age, tumor size, were no significant correlation between pathological type and tumor differentiation (P0.05), and correlated to the clinical stage of ovarian cancer patients is closely related to a statistically significant difference (P0.05); the average percentage after surgery CD4+CD25+CD127-/lowTregs in peripheral blood was (12.243 + 4.213)%, compared with the preoperative decreased, the difference was statistically significant (P0.05); the expression of CD33+HLA-DR-/lowMDSCs in peripheral blood of CD4+ CD25+CD127-/low and Tregs 3. in patients with ovarian cancer have significant correlation (n=72, r=0.0563, P0.05); Thl cytokines IL-2 4. ovary cancer patients in the serum, IFN- gamma levels were significantly lower than the normal people (P0.01), and Th2 cytokines IL-6, IL-10 levels were significantly higher than those in normal people (P0.01), IL-4, TNF level and the health of people and there is no explicit The differences in the serum of patients with early IL-2. And, IFN- gamma levels were significantly higher than those in patients with advanced, and IL-6, the expression level of IL-10 was lower than that in patients with advanced ovarian cancer patients. Conclusion the peripheral blood cells of CD33+HLA-DR-/low MDSCs immune suppression and CD4+CD25+CD127-/lowTregs content were significantly increased compared with healthy controls, the expression of the two genes show significant correlation Thl, and cytokine levels decreased, Th2 increased cytokine levels, suggesting that the formation of immune suppression in patients with ovarian cancer, ovarian cancer and unique for immune regulation mechanism to human ovarian cancer immunodeficiency, provided the experimental basis and method to effectively improve prognosis of ovarian cancer.

【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R737.31

【共引文獻(xiàn)】

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3 師龍;環(huán)磷酰胺對乳腺癌BALB/c小鼠腫瘤及轉(zhuǎn)移淋巴結(jié)中Treg的影響[D];河北醫(yī)科大學(xué);2011年

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9 周莉;CD4~+CD25~+T調(diào)節(jié)細(xì)胞在慢性粒細(xì)胞性白血病中的表達(dá)及臨床意義[D];中南大學(xué);2008年

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