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      胃癌患者外周血T淋巴細(xì)胞亞群及NK細(xì)胞受體表達(dá)水平分析

      2022-04-02 16:10:48雷澤洪林忠順李榮崗區(qū)衛(wèi)林梁萍娟
      關(guān)鍵詞:T淋巴細(xì)胞亞群胃癌

      雷澤洪 林忠順 李榮崗 區(qū)衛(wèi)林 梁萍娟

      【摘要】 目的:研究胃癌患者外周血T淋巴細(xì)胞亞群及NK細(xì)胞受體表達(dá)水平。方法:將2018年1月-2020年12月江門(mén)市中心醫(yī)院收治的142例胃癌患者納入本研究,另納入58例健康體檢者作為對(duì)照組,使用流式細(xì)胞儀檢測(cè)外周血T淋巴細(xì)胞亞群(CD8+、CD4+、CD3+、CD4+/CD8+)分布情況和外周血NK細(xì)胞受體(NKG2D、NKp30、NKG2A、CD158a)表達(dá)情況。結(jié)果:胃癌組患者外周血CD3+T細(xì)胞、CD4+T細(xì)胞、CD4+/CD8+比值較對(duì)照組均明顯下降(P<0.05),CD8+T細(xì)胞比例較對(duì)照組則明顯升高(P<0.05);NK細(xì)胞活化性受體NKG2D和NKp30表達(dá)較對(duì)照組均明顯下降(P<0.05),抑制性受體NKG2A和CD158a表達(dá)較對(duì)照組均明顯升高(P<0.05)。腫瘤直徑≥5 cm、低分化、Ⅲ~Ⅳ期、淋巴結(jié)轉(zhuǎn)移、深層浸潤(rùn)的胃癌患者外周血CD3+T細(xì)胞、CD4+T細(xì)胞、CD4+/CD8+比值、NK細(xì)胞活化性受體NKG2D和NKp30表達(dá)較腫瘤直徑<5 cm、中高分化、Ⅰ~Ⅱ期、無(wú)淋巴結(jié)轉(zhuǎn)移、無(wú)深層浸潤(rùn)均明顯下降(P<0.05),CD8+T細(xì)胞比例、NK細(xì)胞抑制性受體NKG2A和CD158a表達(dá)較腫瘤直徑<5 cm、中高分化、Ⅰ~Ⅱ期、無(wú)淋巴結(jié)轉(zhuǎn)移、無(wú)深層浸潤(rùn)均明顯升高(P<0.05)。結(jié)論:胃癌患者外周血T淋巴細(xì)胞亞群分布紊亂,外周血NK細(xì)胞活化性受體表達(dá)降低,抑制性受體表達(dá)升高,且與胃癌的發(fā)生發(fā)展有關(guān),檢測(cè)胃癌患者外周血T淋巴細(xì)胞亞群和NK細(xì)胞受體表達(dá)有助于評(píng)估細(xì)胞免疫功能、指導(dǎo)臨床治療和評(píng)價(jià)預(yù)后。

      【關(guān)鍵詞】 胃癌 T淋巴細(xì)胞亞群 NK細(xì)胞受體

      Expression of T Lymphocyte Subsets and NK Cell Receptors in Peripheral Blood of Patients with Gastric Cancer/LEI Zehong, LIN Zhongshun, LI Ronggang, OU Weilin, LIANG Pingjuan. //Medical Innovation of China, 2022, 19(08): 019-023

      [Abstract] Objective: To study the expression of T lymphocyte subsets and NK cell receptors in peripheral blood of patients with gastric cancer. Method: A total of 142 patients with gastric cancer treated in Jiangmen Central Hospital from January 2018 to December 2020 were included in this study, and 58 healthy people were included as the control group. The distribution of T lymphocyte subsets (CD8+, CD4+, CD3+, CD4+/CD8+) and the expression of NK cell receptor (NKG2D, NKp30, NKG2A, CD158a) in peripheral blood were detected by flow cytometry. Result: The peripheral blood CD3+ T cells, CD4+ T cells and CD4+/CD8+ ratio in the gastric cancer group were significantly lower than those in the control group (P<0.05), and the proportion of CD8+ T cells was significantly higher than that in the control group (P<0.05); the expressions of NK cell activating receptors NKG2D and NKp30 in peripheral blood of patients with gastric cancer were significantly lower than those in the control group (P<0.05), and the expressions of inhibitory receptors NKG2A and CD158a were significantly higher than those in the control group (P<0.05). The expression of CD3+ T cells, CD4+ T cells, CD4+/CD8+ ratio, NKG2D and NKp30 in peripheral blood of gastric cancer patients with tumor diameter ≥5 cm, low differentiation, stage Ⅲ-Ⅳ, lymph node metastasis and deep infiltration were higher than those of tumor diameter <5 cm, medium and high differentiation, stage Ⅰ-Ⅱ, no lymph node metastasis, no deep infiltration were significantly decreased (P<0.05); the proportion of CD8+ T cells and the expression of NK cell suppressor receptor NKG2A and CD158a in peripheral blood of gastric cancer patients with tumor diameter ≥5 cm, low differentiation, stage Ⅲ-Ⅳ, lymph node metastasis and deep infiltration were higher than those of tumor diameter <5 cm, medium and high differentiation, stage Ⅰ-Ⅱ, no lymph node metastasis, no deep infiltration were significantly increased (P<0.05). Conclusion: The distribution of T lymphocyte subsets in peripheral blood of patients with gastric cancer is disordered, the expression of activated receptor and inhibitory receptor of NK cells in peripheral blood is decreased and increased, which is related to the occurrence and development of gastric cancer, the detection of T lymphocyte subsets and NK cell receptor expression in peripheral blood of patients with gastric cancer is helpful to evaluate cellular immune function, guide clinical treatment and evaluate prognosis.

      [Key words] Gastric cancer T lymphocyte subsets NK cell receptor

      First-author’s address: Jiangmen Central Hospital, Guangdong Province, Jiangmen 529000, China

      doi:10.3969/j.issn.1674-4985.2022.08.005

      胃癌是常見(jiàn)的惡性腫瘤之一,發(fā)病率和死亡率呈上升趨勢(shì),預(yù)后較差[1-2]。近年來(lái)腫瘤免疫學(xué)在腫瘤研究中獲得了越來(lái)越多的關(guān)注,腫瘤的發(fā)生發(fā)展與患者免疫功能關(guān)系密切[3-4]。T淋巴細(xì)胞可分為免疫功能不同的亞群,其中CD4+、CD8+在生理狀態(tài)下保持動(dòng)態(tài)的平衡,共同作用促使機(jī)體免疫功能處于穩(wěn)定狀態(tài)[5-6]。自然殺傷(NK)細(xì)胞是機(jī)體重要的免疫細(xì)胞可直接殺傷腫瘤細(xì)胞,其細(xì)胞表面表達(dá)活化性受體和抑制性受體[7]。腫瘤細(xì)胞可通過(guò)調(diào)控NK細(xì)胞受體表達(dá),而影響NK細(xì)胞對(duì)腫瘤細(xì)胞的免疫監(jiān)視及清除作用[8-9]。因此,本文擬研究胃癌患者外周血T淋巴細(xì)胞亞群及NK細(xì)胞受體表達(dá)水平,以分析胃癌患者的細(xì)胞免疫功能狀況及臨床意義?,F(xiàn)報(bào)道如下。

      1 資料與方法

      1.1 一般資料 將2018年1月-2020年12月江門(mén)市中心醫(yī)院收治的142例原發(fā)性胃癌患者納入本研究作為胃癌組。納入標(biāo)準(zhǔn):(1)年齡18~75歲,性別不限;(2)符合胃癌診斷標(biāo)準(zhǔn);(3)均接受手術(shù)治療,且術(shù)前均未接受放化療治療;(4)臨床資料完整。排除標(biāo)準(zhǔn):(1)合并其他消化系統(tǒng)相關(guān)疾病者;(2)合并肺、肝、腎等臟器功能障礙者;(3)合并其他部位惡性腫瘤者;(4)合并精神疾病者。另納入58例健康體檢者作為對(duì)照組,其中男32例,女26例,年齡30~72歲,平均(58.25±8.72)歲。納入標(biāo)準(zhǔn):(1)年齡18~75歲,性別不限;(2)健康體檢結(jié)果均顯示正常。排除標(biāo)準(zhǔn):依從性差。本研究經(jīng)醫(yī)院醫(yī)學(xué)倫理委員會(huì)批準(zhǔn),所有入選者均對(duì)本研究知情同意并簽署了知情同意書(shū)。

      1.2 方法

      1.2.1 樣本采集 采集兩組空腹外周靜脈血各兩管,每管采集5 mL,其中一管用于外周血T淋巴細(xì)胞亞群檢測(cè),另一管用于NK細(xì)胞受體表達(dá)檢測(cè),均需在采集后2 h內(nèi)檢測(cè)完畢。

      1.2.2 外周血T淋巴細(xì)胞亞群檢測(cè) 采用美國(guó)BDFacscalibur生產(chǎn)的流式細(xì)胞儀對(duì)兩組血液樣本進(jìn)行T淋巴細(xì)胞亞群檢測(cè),包括CD8+、CD4+、CD3+,并對(duì)CD4+/CD8+進(jìn)行計(jì)算,相關(guān)試劑盒均購(gòu)自北京中杉金橋有限公司。

      1.2.3 外周血NK細(xì)胞受體表達(dá)檢測(cè) 每個(gè)流式管中加入50 μL全血,再加入5 μL anti-CD3-FITC、anti-CD56-APC、anti-CD16-Per CP,然后每管再分別加入5 μL單克隆抗體(anti-NKG2D-PE、anti-NKp30-PE、anti-NKG2A-PE、anti-CD158a-PE),同時(shí)設(shè)置的陰性對(duì)照組。各組樣本經(jīng)充分混勻后,在室溫下放置20 min,再加入細(xì)胞裂解液室溫靜置10 min,再加入PBS震蕩混勻,再用PBS洗滌2次,然后使用流式細(xì)胞儀進(jìn)行上機(jī)檢測(cè)。

      1.3 觀察指標(biāo) 比較兩組外周血T淋巴細(xì)胞亞群、NK細(xì)胞受體表達(dá)差異性,以及不同病理參數(shù)胃癌患者外周血T淋巴細(xì)胞亞群、NK細(xì)胞受體表達(dá)的差異性。

      1.4 統(tǒng)計(jì)學(xué)處理 使用SPSS 20.00處理數(shù)據(jù),符合正態(tài)分布的計(jì)量資料以(x±s)表示,兩組比較采用t檢驗(yàn);計(jì)數(shù)資料以率(%)表示,采用字2檢驗(yàn)。以P<0.05為差異有統(tǒng)計(jì)學(xué)意義。

      2 結(jié)果

      2.1 兩組一般資料比較 胃癌組,其中男77例,女65例;年齡36~75歲,平均(59.04±9.36)歲;分化程度:中高分化81例,低分化61例;TNM分期:Ⅰ~Ⅱ期57例,Ⅲ~Ⅳ期85例;腫瘤直徑1.9~9.8 cm,平均(5.89±1.63)cm;有淋巴結(jié)轉(zhuǎn)移者27例;有深層浸潤(rùn)者39例。對(duì)照組,其中男32例,女26例,年齡30~72歲,平均(58.25±8.72)歲。兩組的年齡、性別相比,差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05),具有可比性。

      2.2 兩組外周血T淋巴細(xì)胞亞群比較 胃癌組患者外周血CD3+T細(xì)胞、CD4+T細(xì)胞、CD4+/CD8+較對(duì)照組均明顯下降,CD8+T細(xì)胞比例較對(duì)照組則明顯升高,差異均有統(tǒng)計(jì)學(xué)意義(P<0.05),見(jiàn)表1。

      2.3 兩組外周血NK細(xì)胞受體表達(dá)比較 胃癌組患者外周血NK細(xì)胞活化性受體NKG2D和NKp30表達(dá)較對(duì)照組均明顯下降,抑制性受體NKG2A和CD158a表達(dá)較對(duì)照組均明顯升高,差異均有統(tǒng)計(jì)學(xué)意義(P<0.05),見(jiàn)表2。

      2.4 不同病理參數(shù)胃癌患者外周血T淋巴細(xì)胞亞群比較 腫瘤直徑≥5 cm、低分化、Ⅲ~Ⅳ期、淋巴結(jié)轉(zhuǎn)移、深層浸潤(rùn)的胃癌患者外周血CD3+T細(xì)胞、CD4+T細(xì)胞、CD4+/CD8+比值較腫瘤直徑<5 cm、中高分化、Ⅰ~Ⅱ期、無(wú)淋巴結(jié)轉(zhuǎn)移、無(wú)深層浸潤(rùn)均明顯下降(P<0.05),CD8+T細(xì)胞比例較腫瘤直徑<5 cm、中高分化、Ⅰ~Ⅱ期、無(wú)淋巴結(jié)轉(zhuǎn)移、無(wú)深層浸潤(rùn)均明顯升高(P<0.05),見(jiàn)表3。

      2.5 不同病理參數(shù)胃癌患者外周血NK細(xì)胞受體表達(dá)比較 腫瘤直徑≥5 cm、低分化、Ⅲ~Ⅳ期、淋巴結(jié)轉(zhuǎn)移、深層浸潤(rùn)的胃癌患者外周血NK細(xì)胞活化性受體NKG2D和NKp30表達(dá)較腫瘤直徑<5 cm、中高分化、Ⅰ~Ⅱ期、無(wú)淋巴結(jié)轉(zhuǎn)移、無(wú)深層浸潤(rùn)均明顯下降(P<0.05),抑制性受體NKG2A和CD158a表達(dá)較腫瘤直徑<5 cm、中高分化、Ⅰ~Ⅱ期、無(wú)淋巴結(jié)轉(zhuǎn)移、無(wú)深層浸潤(rùn)均明顯升高(P<0.05)。見(jiàn)表4。

      3 討論

      胃癌是一種起源于胃黏膜上皮的惡性腫瘤,目前我國(guó)胃癌致死率居惡性腫瘤第三位[10-11]。近年來(lái)的腫瘤免疫學(xué)研究顯示,包括胃癌在內(nèi)的惡性腫瘤的發(fā)生和發(fā)展與機(jī)體免疫功能異常密切相關(guān),而T淋巴細(xì)胞及NK細(xì)胞在腫瘤免疫中發(fā)揮重要作用[12-14]。

      T淋巴細(xì)胞可分為CD4+和CD8+T淋巴細(xì)胞兩個(gè)亞群[15]。在正常生理狀態(tài)下,CD4+和CD8+T淋巴細(xì)胞亞群保持動(dòng)態(tài)平衡以維持機(jī)體正常免疫功能[16]。最近的研究表明,T淋巴細(xì)胞亞群比例不僅可以反映機(jī)體的免疫功能狀態(tài),還可以反映腫瘤微環(huán)境的變化[17-18],因此具有重要的臨床應(yīng)用價(jià)值。本研究結(jié)果顯示,胃癌組患者外周血CD3+T細(xì)胞、CD4+T細(xì)胞、CD4+/CD8+比值較對(duì)照組均明顯下降(P<0.05),CD8+T細(xì)胞比例較對(duì)照組則明顯升高(P<0.05),提示胃癌患者外周血T淋巴細(xì)胞亞群異常/比例失調(diào),導(dǎo)致患者細(xì)胞免疫功能明顯下降而有助于腫瘤的發(fā)生。進(jìn)一步分析不同病理參數(shù)胃癌患者外周血T淋巴細(xì)胞亞群分布發(fā)現(xiàn),腫瘤越大、分化程度越低、分期越晚、發(fā)生淋巴結(jié)轉(zhuǎn)移及深層浸潤(rùn)的胃癌患者外周血CD3+T細(xì)胞、CD4+T細(xì)胞、CD4+/CD8+比值越低,CD8+T細(xì)胞比例越高,提示胃癌患者惡性程度越高,T淋巴細(xì)胞亞群分布越紊亂。

      NK細(xì)胞對(duì)腫瘤細(xì)胞具有直接殺傷作用,而腫瘤細(xì)胞可通過(guò)影響受體表達(dá)而影響NK細(xì)胞的殺傷作用[19-20]。本研究結(jié)果顯示,胃癌組患者NK細(xì)胞活化性受體NKG2D和NKp30表達(dá)較對(duì)照組均明顯下降(P<0.05),抑制性受體NKG2A和CD158a表達(dá)較對(duì)照組均明顯升高(P<0.05),這與文獻(xiàn)[21]的報(bào)道結(jié)果相符合。本研究進(jìn)一步分析了不同病理參數(shù)胃癌患者NK細(xì)胞受體表達(dá)情況,結(jié)果顯示腫瘤體積越大、分化程度越低、分期越晚、發(fā)生淋巴結(jié)轉(zhuǎn)移及深層浸潤(rùn)的胃癌患者NK細(xì)胞活化性受體NKG2D和NKp30表達(dá)越低,抑制性受體NKG2A和CD158a表達(dá)越高,提示胃癌患者惡性程度越高,NK細(xì)胞的活性降低,免疫監(jiān)視功能越弱。

      綜上所述,胃癌患者外周血T淋巴細(xì)胞亞群分布紊亂,NK細(xì)胞活化性受體表達(dá)降低,抑制性受體表達(dá)升高,且與胃癌的發(fā)生發(fā)展有關(guān),檢測(cè)胃癌患者外周血T淋巴細(xì)胞亞群和NK細(xì)胞受體表達(dá)有助于評(píng)估細(xì)胞免疫功能、指導(dǎo)臨床治療和評(píng)價(jià)預(yù)后。

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      (收稿日期:2021-09-02) (本文編輯:張爽)

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