胡叢崗,湯國(guó)軍,王建軍,童 骎

(金華廣福醫(yī)院胃腸外科，浙江金華 321000)

原發(fā)性肝癌患者腫瘤轉(zhuǎn)移與T細(xì)胞亞群及其細(xì)胞因子的相關(guān)性分析

胡叢崗,湯國(guó)軍,王建軍,童 骎

(金華廣福醫(yī)院胃腸外科，浙江金華 321000)

目的 探討原發(fā)性肝癌患者腫瘤轉(zhuǎn)移與T細(xì)胞亞群及其細(xì)胞因子的相關(guān)性。方法 2014年1月至2016年1月前瞻性收集原發(fā)性肝癌患者97例，根據(jù)患者是否發(fā)生轉(zhuǎn)移，將患者分為轉(zhuǎn)移組和非轉(zhuǎn)移組，其中轉(zhuǎn)移組38例，非轉(zhuǎn)移組59例。所有患者均取得手術(shù)標(biāo)本，使用流式細(xì)胞儀測(cè)定肝癌組織、癌旁組織和外周血CD4+、CD8+T細(xì)胞比例，同時(shí)使用酶聯(lián)免疫吸附試驗(yàn)測(cè)定外周血中白細(xì)胞介素(IL)-6、IL-10、腫瘤壞死因子-α(TNF-α)和γ-干擾素(IFN-γ)水平。結(jié)果 與非轉(zhuǎn)移組相比，轉(zhuǎn)移組患者肝癌組織中CD4+T細(xì)胞比例顯著升高(P=0.002)；CD8+T細(xì)胞顯著降低(P=0.015)。兩組患者癌旁組織中CD4+T細(xì)胞比例差異無統(tǒng)計(jì)學(xué)意義P=0.328)。轉(zhuǎn)移組患者癌旁組織中CD8+T細(xì)胞比例顯著高于非轉(zhuǎn)移組(P=0.021)。兩組患者外周血中CD8+T細(xì)胞比例差異無統(tǒng)計(jì)學(xué)意義(P=0.362)。轉(zhuǎn)移組患者外周血CD4+T細(xì)胞比例顯著低于非轉(zhuǎn)移組(P=0.032)。與非轉(zhuǎn)移組比較，轉(zhuǎn)移組患者外周血IL-6水平顯著降低(P=0.012)；IL-10水平顯著升高(P=0.006)；TNF-α水平顯著降低(P=0.000)；IFN-γ水平顯著降低(P=0.035)。結(jié)論 原發(fā)性肝癌患者腫瘤轉(zhuǎn)移存在明顯的T細(xì)胞亞群和細(xì)胞因子平衡失調(diào)。

原發(fā)性肝癌；腫瘤轉(zhuǎn)移；T細(xì)胞亞群；細(xì)胞因子；免疫抑制

我國(guó)乙型肝炎發(fā)生率較高，長(zhǎng)期慢性的乙型肝炎病毒感染可導(dǎo)致肝硬化，進(jìn)而可導(dǎo)致肝癌[1-2]。另外，由于嗜酒人群得不到有效控制，酒精性肝硬化等導(dǎo)致的肝癌也較為常見[3]。目前，肝癌是中老年患者最常見的惡性腫瘤之一，早期即可肝內(nèi)轉(zhuǎn)移、肝門轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移[4-6]。轉(zhuǎn)移是肝癌患者臨床預(yù)后的決定性因素。因此探討原發(fā)性肝癌患者腫瘤轉(zhuǎn)移的相關(guān)因素具有十分重要的意義。免疫系統(tǒng)失衡在腫瘤的發(fā)生和發(fā)展中具有十分重要的臨床意義。目前在其他腫瘤的研究中已證實(shí)腫瘤患者存在免疫抑制，主要表現(xiàn)為Th1/Th2細(xì)胞功能失衡[7-9]。為探討免疫系統(tǒng)在原發(fā)性肝癌患者中的作用，2013年林澤偉等[10]研究發(fā)現(xiàn)肝癌組織中、癌旁正常組織和健康肝組織中CD3+CD4+T細(xì)胞占浸潤(rùn)淋巴細(xì)胞的比例分別為(22.31±3.68)%、(10.69±2.47)%和(4.21±4.26)%，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)，而CD3+CD8+T細(xì)胞占浸潤(rùn)淋巴細(xì)胞的比例分別為(26.10±5.82)%、(21.82±2.70)%和(41.31±14.01)%，差異有統(tǒng)計(jì)學(xué)意義(P=0.000)。CD8+T細(xì)胞是抗腫瘤免疫反應(yīng)中重要的效應(yīng)細(xì)胞，受炎性因子刺激可分化成細(xì)胞毒性T淋巴細(xì)胞，進(jìn)而介導(dǎo)腫瘤細(xì)胞的殺傷作用[11-12]。在肝癌組織中CD8+T細(xì)胞水平減低，表明其殺傷作用降低，有利于腫瘤細(xì)胞的生長(zhǎng)和轉(zhuǎn)移。而CD4+T細(xì)胞可分化為調(diào)節(jié)性T細(xì)胞，介導(dǎo)腫瘤細(xì)胞的免疫耐受[13-15]。因此肝癌組織中CD4+和CD8+T細(xì)胞平衡的失調(diào)可能參與了肝癌細(xì)胞的生長(zhǎng)和轉(zhuǎn)移。上述研究證實(shí)了原發(fā)性肝癌的發(fā)生與免疫抑制相關(guān)，但是免疫抑制與肝癌細(xì)胞轉(zhuǎn)移的關(guān)系如何，相關(guān)研究缺乏。本研究旨在探討原發(fā)性肝癌患者腫瘤細(xì)胞轉(zhuǎn)移與T細(xì)胞亞群及其細(xì)胞因子的關(guān)聯(lián)性。

1 資料與方法

1.1 一般資料 2014年1月至2016年1月前瞻性收集本院收治的原發(fā)性肝癌患者，納入標(biāo)準(zhǔn)：(1)原發(fā)性肝癌；(2)可獲取手術(shù)病理標(biāo)本；(3)年齡大于或等于18歲且小于或等于65歲；(4)同意參與本研究。排除標(biāo)準(zhǔn)：(1)復(fù)發(fā)性肝癌；(2)轉(zhuǎn)移性肝癌；(3)心、腦、肺、腎等臟器功能不全；(4)合并急性或慢性感染；(5)合并其他惡性腫瘤；(6)原發(fā)性免疫功能缺陷；(7)血液系統(tǒng)或內(nèi)分泌系統(tǒng)疾??；(8)甲狀腺功能異常；(9)原發(fā)性肝癌多中心發(fā)生病灶(各瘤灶相對(duì)獨(dú)立、周圍包括高分化區(qū)域或存在高分化向低分化過渡的區(qū)域或多發(fā)瘤灶間瘤細(xì)胞亞型不同，對(duì)于不能區(qū)分的肝癌多中心發(fā)生病灶和肝內(nèi)轉(zhuǎn)移病灶給予排除)；(10)不配合治療。研究期間，根據(jù)納入標(biāo)準(zhǔn)和排除標(biāo)準(zhǔn)，共納入原發(fā)性肝癌患者97例，根據(jù)入院時(shí)患者是否發(fā)生肝癌轉(zhuǎn)移，將患者分為轉(zhuǎn)移組(合并有肝內(nèi)、肝門或遠(yuǎn)處轉(zhuǎn)移，對(duì)于肝內(nèi)轉(zhuǎn)移的患者，肝內(nèi)轉(zhuǎn)移的診斷要點(diǎn)：肝內(nèi)多發(fā)病灶、瘤灶與門靜脈瘤栓相連、較大瘤灶周圍伴隨多發(fā)的衛(wèi)星病灶或體積較小的實(shí)體瘤病灶與體積較大的實(shí)體瘤病灶位置接近，組織學(xué)特征相似)和非轉(zhuǎn)移組(肝內(nèi)單結(jié)節(jié)病灶，經(jīng)病理確診為原發(fā)性肝癌)，其中轉(zhuǎn)移組38例，非轉(zhuǎn)移組59例。轉(zhuǎn)移組男21例，女17例，年齡35～65歲，平均(51.82±8.92)歲，21例合并肝內(nèi)轉(zhuǎn)移，18例合并肝門轉(zhuǎn)移，7例合并遠(yuǎn)處轉(zhuǎn)移(其中8例為多處轉(zhuǎn)移)；非轉(zhuǎn)移組男34例，女25例，年齡37～64歲，平均(50.88±8.12)歲，無患者發(fā)生肝內(nèi)、肝門或遠(yuǎn)處轉(zhuǎn)移。兩組患者的性別和年齡等差異無統(tǒng)計(jì)學(xué)意義(P>0.05)，具有可比性。本研究中所有患者均知情同意并簽署知情同意書，本研究通過本院倫理委員會(huì)批準(zhǔn)。

1.2 數(shù)據(jù)收集 觀察指標(biāo)包括肝癌組織中、癌旁組織和外周血中CD4+T細(xì)胞和CD8+T細(xì)胞，及外周血中白細(xì)胞介素(IL)-6、IL-10、腫瘤壞死因子α(TNF-α)和γ-干擾素(IFN-γ)。

1.3 檢測(cè)方法 (1)肝癌組織和肝癌旁組織CD4+T細(xì)胞和CD8+T細(xì)胞：術(shù)中留取肝癌組織和肝癌旁組織標(biāo)本(距離腫瘤組織大于或等于5 cm)，將標(biāo)本置于培養(yǎng)皿中，使用0.9%的氯化鈉溶液沖洗標(biāo)本，取新鮮的組織標(biāo)本，用組織剪將標(biāo)本剪成1 mm3左右的組織塊，酶消化后用PBS溶液反復(fù)沖洗，留取細(xì)胞懸液，再低速離心除去細(xì)胞團(tuán)及碎片。使用離心機(jī)(2 000 r/min)離心細(xì)胞懸液10 min，取細(xì)胞沉淀并將其混浴PBS溶液中，使用密度梯度離心法將淋巴細(xì)胞分離。PBS溶液再次洗滌淋巴細(xì)胞，并在室溫下離心。定容后計(jì)入單克隆抗體，室內(nèi)常溫下反應(yīng)30 min，60 min內(nèi)進(jìn)行流式細(xì)胞檢測(cè)，儀器：Epics XL型流式細(xì)胞儀(美國(guó)Beckman Coulter公司)。(2)外周血CD4+和CD8+T細(xì)胞：抽取患者靜脈血5 mL，留存在乙二胺四乙酸二鈉試管中，加入單克隆抗體后室溫下避光反應(yīng)30 min后進(jìn)行流式細(xì)胞儀檢測(cè)，儀器：Epics XL型流式細(xì)胞儀(美國(guó)Beckman Coulter公司)。(3)外周血中IL-6、IL-10、TNF-α和IFN-γ：抽取患者靜脈血5 mL，3 000 r/min離心后取上層血清置于-20 ℃的冷柜中保存待檢，使用ELISA法檢測(cè)IL-6、IL-10、TNF-α和IFN-γ，ELISA試劑盒購(gòu)自江蘇菲亞生物科技有限公司。

2 結(jié) 果

2.1 兩組患者肝癌組織中T細(xì)胞亞群分析 與非轉(zhuǎn)移組相比，轉(zhuǎn)移組患者肝癌組織中CD4+T細(xì)胞比例顯著升高[(24.67±4.82)%vs.(19.83±3.27)%,P=0.002]；CD8+T細(xì)胞顯著降低[(20.82±3.08)%vs.(24.76±2.88)%,P=0.015]。

2.2 兩組患者癌旁組織T細(xì)胞亞群分析 兩組患者癌旁組織中CD4+T細(xì)胞比例差異無統(tǒng)計(jì)學(xué)意義[(11.99±2.48)%vs.(11.32±1.98)%,P=0.328]。轉(zhuǎn)移組患者癌旁組織中CD8+T細(xì)胞比例顯著高于非轉(zhuǎn)移組[(18.83±4.25)%vs.(21.45±4.82)%,P=0.021)]。

2.3 外周血中T細(xì)胞亞群分析 兩組患者外周血中CD8+T細(xì)胞比例差異無統(tǒng)計(jì)學(xué)意義[(29.33±4.74)%vs.(30.03±3.89)%,P=0.362]。轉(zhuǎn)移組患者外周血CD4+T細(xì)胞比例顯著低于非轉(zhuǎn)移組[(24.56±3.24)%vs.(28.76±4.12)%,P=0.032)]。

2.4 兩組患者外周血細(xì)胞因子水平比較 與非轉(zhuǎn)移組比較，轉(zhuǎn)移組患者IL-6水平顯著降低(P=0.012)；IL-10水平顯著升高(P=0.006)；TNF-α水平顯著降低(P=0.000)；IFN-γ顯著降低(P=0.035)。見表1。

表1 兩組患者外周血細(xì)胞因子水平比較

3 討 論

免疫系統(tǒng)介導(dǎo)的細(xì)胞免疫在機(jī)體對(duì)抗腫瘤細(xì)胞中起到一個(gè)關(guān)鍵作用。腫瘤組織中淋巴細(xì)胞的浸潤(rùn)有助于限制腫瘤細(xì)胞生長(zhǎng)及轉(zhuǎn)移，進(jìn)而改善患者臨床預(yù)后。2016年Sobottka等[16]研究顯示乳腺癌組織中淋巴細(xì)胞浸潤(rùn)有助于降低患者腫瘤細(xì)胞轉(zhuǎn)移風(fēng)險(xiǎn)。同一年Romero等[17]研究同樣證實(shí)了淋巴細(xì)胞浸潤(rùn)在非小細(xì)胞肺癌中的作用。目前，關(guān)于原發(fā)性肝癌患者組織中淋巴細(xì)胞浸潤(rùn)情況、癌旁組織中淋巴細(xì)胞浸潤(rùn)情況、外周血中T細(xì)胞亞群及其細(xì)胞因子變化與腫瘤細(xì)胞轉(zhuǎn)移的關(guān)聯(lián)性尚不清楚，且相關(guān)研究缺乏，因此筆者設(shè)計(jì)了本研究。CD4+和CD8+T細(xì)胞是T淋巴細(xì)胞的主要亞群，其水平可以較好地反映患者體內(nèi)免疫狀態(tài)。機(jī)體對(duì)腫瘤細(xì)胞的免疫應(yīng)答，主要通過CD8+T細(xì)胞，可以產(chǎn)生IFN-γ，提高機(jī)體對(duì)腫瘤細(xì)胞的殺傷作用[12,18]。本研究顯示轉(zhuǎn)移組IFN-γ水平降低，腫瘤組織和癌旁組織中CD8+T細(xì)胞水平降低，表明原發(fā)性肝癌合并腫瘤細(xì)胞轉(zhuǎn)移的患者對(duì)腫瘤細(xì)胞的殺傷作用較低，其可能介導(dǎo)了腫瘤細(xì)胞的轉(zhuǎn)移。另外IL-10主要由Th2細(xì)胞分泌，可以抑制CD4+T細(xì)胞向Th1漂移，進(jìn)而促進(jìn)Th1/Th2細(xì)胞免疫向Th2免疫漂移，進(jìn)而介導(dǎo)患者的免疫抑制[19-21]。本研究中轉(zhuǎn)移組患者IL-10水平升高，表明CD4+T細(xì)胞更傾向于向Th2細(xì)胞分化，進(jìn)而促進(jìn)肝癌細(xì)胞的生長(zhǎng)和轉(zhuǎn)移。值得注意的是，本研究顯示轉(zhuǎn)移組肝癌組織中CD4+T細(xì)胞水平升高，而外周血中CD4+T細(xì)胞水平下降。腫瘤組織中CD4+T細(xì)胞可以在IL-10等炎性因子的作用下，分化為Treg細(xì)胞，Treg細(xì)胞升高是腫瘤免疫耐受的重要基礎(chǔ)[22-23]。外周血中CD4+T細(xì)胞降低，結(jié)合其他細(xì)胞因子的結(jié)果，表明Th1/Th2細(xì)胞免疫失衡不僅表現(xiàn)為細(xì)胞免疫向Th2漂移，還表現(xiàn)為Th1/Th2細(xì)胞免疫能力整體降低。另外，IL-6和TNF-α均是促炎因子。如IL-6由纖維母細(xì)胞、單核/巨噬細(xì)胞、T淋巴細(xì)胞、B淋巴細(xì)胞、上皮細(xì)胞等多種炎性細(xì)胞產(chǎn)生，刺激參與免疫反應(yīng)的細(xì)胞增殖、分化并提高其免疫功能，其水平降低與免疫抑制有關(guān)[24-25]。本研究顯示轉(zhuǎn)移組患者IL-6和TNF-α水平均降低，從另一方面證實(shí)了免疫抑制在原發(fā)性肝癌患者轉(zhuǎn)移中的作用。

綜上所述，原發(fā)性肝癌患者腫瘤轉(zhuǎn)移存在明顯的T細(xì)胞亞群和細(xì)胞因子平衡失調(diào)。

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Relationship between tumor metastasis with T cell subsets and cytokines in patients with primary hepatocellular carcinoma

HuConggang,TangGuojun,WangJianjun,TongQin

(DepartmentofGastrointestinalSurgery,JinhuaGuangfuHospital,Jinhua,Zhejiang321000,China)

Objective To investigate the correlation between tumor metastasis with T cell subsets and cytokines in the patients with primary hepatocellular carcinoma(HCC).Methods Ninety-seven cases of primary HCC were prospectively collected from January 2014 to January 2016 and assigned into the metastasis group (38 cases) and non-metastasis group(59 cases) according to whether suffering from metastasis.Surgical specimens were obtained from all patients and flow cytometry was used to detect the CD4+,CD8+T cell proportion in HCC tissue,paracancerous tissues and peripheral blood.Moreover,ELISA was adopted to detect the peripheral blood IL-6,IL-10,TNF-α and IFN-γ levels.Results Compared with the non-metastasis group,the CD4+T cell proportion of HCC tissue in the metastasis group was significantly increased(P=0.02),while the CD8+T cells were significantly decreased (P=0.015).There was no statistical difference in CD4+T cells proportion in the paracancerous tissue between the two groups (P=0.328).However the CD8+T cells proportion of paracancerous tissue in the metastasis group was significantly higher than that in the non-metastasis group (P=0.021).There was no statistically significant difference in the proportion of CD8+T cells in peripheral blood of the two groups (P=0.362).The proportion of CD4+T cells in peripheral blood of the metastatic group was significantly lower than that in non-metastasis group (P=0.032).When compared with non-metastasis group,the metastasis group got a decreased level of peripheral blood IL-6 (P=0.012);while the IL-10 level was significantly increased (P=0.006);the TNF-α level and IFN-γ level were significantly decreased(P=0.000,P=0.035).Conclusion The patients with primary HCC have obvious T cell subsets and cytokines imbalance.

primary liver cancer;tumor metastasis;T cell subsets;cytokines;immune suppression

胡叢崗(1977-)，本科，主治醫(yī)師，主要從事腫瘤外科工作。

10.3969/j.issn.1671-8348.2017.16.017

R735.7

A

1671-8348(2017)16-2215-03

2017-01-30

2017-04-04)

論著·臨床研究