乳腺浸潤性導(dǎo)管癌微環(huán)境中CD4和CD8陽性T細(xì)胞表達(dá)與血管新生的關(guān)聯(lián)性分析

拉 宗,王建霞,崔 倪,李明月,邢樹剛,任 博,張麗紅,李 偉,李玉林

(1.吉林大學(xué)基礎(chǔ)醫(yī)學(xué)院病理學(xué)系病理生物學(xué)教育部重點(diǎn)實(shí)驗(yàn)室,吉林長春 130021;2.西藏大學(xué)醫(yī)學(xué)院病理學(xué)教研室,西藏拉薩 850000)

乳腺浸潤性導(dǎo)管癌微環(huán)境中CD4和CD8陽性T細(xì)胞表達(dá)與血管新生的關(guān)聯(lián)性分析

拉 宗1,2,王建霞1,崔 倪?,李明月1,邢樹剛1,任 博1,張麗紅1,李 偉1,李玉林1

(1.吉林大學(xué)基礎(chǔ)醫(yī)學(xué)院病理學(xué)系病理生物學(xué)教育部重點(diǎn)實(shí)驗(yàn)室,吉林長春 130021;2.西藏大學(xué)醫(yī)學(xué)院病理學(xué)教研室,西藏拉薩 850000)

目的:檢測(cè)乳腺浸潤性導(dǎo)管癌微環(huán)境中CD4及CD8陽性T淋巴細(xì)胞的表達(dá),探討其與乳腺癌間質(zhì)微血管密度(MVD)的關(guān)系。方法:應(yīng)用免疫組織化學(xué)SP法檢測(cè)37例乳腺浸潤性導(dǎo)管癌組織及10例癌旁組織中CD4、CD8及CD34的表達(dá),并對(duì)其在癌及癌旁組織中的表達(dá)差異進(jìn)行分析。采用Spearman相關(guān)性分析方法分析CD4、CD8及CD4與CD8陽性表達(dá)率的比值(CD4/CD8比值)與MVD的相關(guān)性。結(jié)果:CD4在乳腺浸潤性導(dǎo)管癌組織中的陽性表達(dá)率為(22.63±11.53)%,低于癌旁組織[(34.09±10.41)%](P＜0.05),隨著乳腺癌組織學(xué)級(jí)別的升高,CD4陽性表達(dá)率逐漸降低(P＜0.05)。CD8在乳腺浸潤性導(dǎo)管癌組織中的陽性表達(dá)率為(14.27± 9.03)%,高于癌旁組織[(10.51±1.88)%],但差異無統(tǒng)計(jì)學(xué)意義(P＞0.05),隨著乳腺癌組織學(xué)級(jí)別的升高, CD8陽性表達(dá)率逐漸升高(P＜0.01)。在癌旁組織及乳腺浸潤性導(dǎo)管癌組織中CD4/CD8比值分別為3.24±1.02 和2.16±2.17,兩者比較差異無統(tǒng)計(jì)學(xué)意義(P＞0.05);隨著乳腺癌組織學(xué)級(jí)別的升高CD4/CD8比值降低(P＜0.01)。乳腺浸潤性導(dǎo)管癌組織中的MVD值明顯高于癌旁組織(P＜0.05),并且隨乳腺癌組織學(xué)級(jí)別的升高, MVD值呈遞增趨勢(shì)。相關(guān)性分析,MVD與CD4陽性表達(dá)率呈負(fù)相關(guān)關(guān)系(r＝－1.000,P＜0.001),與CD8陽性表達(dá)率呈正相關(guān)關(guān)系(r＝0.984,P＜0.001),與CD4/CD8比值呈負(fù)相關(guān)關(guān)系(r＝－0.984,P＜0.001)。結(jié)論:乳腺浸潤性導(dǎo)管癌間質(zhì)CD4陽性T淋巴細(xì)胞減少,CD8陽性T淋巴細(xì)胞增多,CD4/CD8比值下降,提示在乳腺癌微環(huán)境中T細(xì)胞處于免疫抑制狀態(tài)。

乳腺腫瘤;T淋巴細(xì)胞;腫瘤血管新生;CD4;CD8

腫瘤微環(huán)境由腫瘤實(shí)質(zhì)和間質(zhì)兩部分構(gòu)成,腫瘤間質(zhì)包括免疫細(xì)胞、炎癥細(xì)胞、成纖維細(xì)胞和微血管等。腫瘤微環(huán)境中的組成成分在腫瘤的生長、浸潤和轉(zhuǎn)移等破壞機(jī)體正常組織過程中起著不可忽視的作用[1]。腫瘤從發(fā)生到轉(zhuǎn)移的整個(gè)過程是腫瘤細(xì)胞與間質(zhì)相互作用的結(jié)果。微環(huán)境中的免疫狀態(tài)尤其是細(xì)胞介導(dǎo)的免疫反應(yīng)能直接反應(yīng)機(jī)體局部對(duì)腫瘤的反應(yīng)狀況[2-3]。有文獻(xiàn)[4]報(bào)道:一些惡性腫瘤微環(huán)境中免疫細(xì)胞及其分泌的相關(guān)因子參與腫瘤生長侵襲的調(diào)節(jié),惡性腫瘤微環(huán)境中的免疫細(xì)胞與腫瘤間質(zhì)血管新生也存在相互作用關(guān)系。綜合分析腫瘤微環(huán)境中腫瘤細(xì)胞、腫瘤浸潤淋巴細(xì)胞以及腫瘤間質(zhì)新生血管之間相互作用的研究尚未見文獻(xiàn)報(bào)道。本實(shí)驗(yàn)應(yīng)用人乳腺癌組織標(biāo)本,通過免疫組織化學(xué)方法檢測(cè)乳腺癌組織微環(huán)境中免疫細(xì)胞的類型及數(shù)量,并分析其與腫瘤血管新生之間的關(guān)系。

1 材料與方法

1.1 組織標(biāo)本收集吉林大學(xué)第一醫(yī)院2010年9月—2011年11月行外科手術(shù)且經(jīng)臨床病理醫(yī)生確診的乳腺浸潤性導(dǎo)管癌組織標(biāo)本37例,其中Ⅰ級(jí)8例、Ⅱ級(jí)25例、Ⅲ級(jí)4例。37例標(biāo)本均包括癌組織以及癌旁組織,取材時(shí),癌旁組織為距癌結(jié)節(jié)2 cm以內(nèi)的帶乳腺腺體的正常組織,且避開壞死區(qū)。所有研究對(duì)象術(shù)前均未接受任何治療,均無糖尿病、類風(fēng)濕和甲狀腺功能亢進(jìn)等自身免疫性疾病史及免疫治療史,年齡35～70歲,平均年齡48歲。所采集的標(biāo)本均經(jīng)患者知情同意且經(jīng)吉林大學(xué)第一醫(yī)院倫理委員會(huì)的同意。

1.2 免疫組織化學(xué)染色采用免疫組織化學(xué)染色SP法,CD4多克隆抗體購自美國Bioworld技術(shù)公司,CD8單克隆抗體購自美國Epitomics公司, CD34單克隆抗體購自北京中山技術(shù)公司,SP免疫組織化學(xué)試劑盒和DAB顯色劑均購自福州邁新生物技術(shù)有限公司。石蠟切片脫蠟至水化,用枸櫞酸鹽修復(fù)液進(jìn)行抗原修復(fù),冷卻至室溫后水洗,CD4抗體1∶200倍稀釋,CD8抗體1∶800倍稀釋, CD34抗體為即用型,4℃孵育過夜,其他實(shí)驗(yàn)步驟按SP試劑盒說明書進(jìn)行。以已知陽性組織作為陽性對(duì)照,以PBS為一抗作為陰性對(duì)照。

1.3 結(jié)果判定標(biāo)準(zhǔn)CD4及CD8陽性表達(dá)顆粒定位于淋巴細(xì)胞膜,結(jié)果判斷標(biāo)準(zhǔn)參照文獻(xiàn)[5],淋巴細(xì)胞膜中出現(xiàn)棕黃色為陽性表達(dá),對(duì)陽性細(xì)胞所占百分率進(jìn)行評(píng)分:1分為≤10%,2分為11%～30%,3分為31%～50%,4分為＞50%;＜3分為陰性,≥3分為陽性。

MVD結(jié)果的判定:以CD34表達(dá)陽性作為微血管的標(biāo)志,CD34陽性染色顆粒定位于血管內(nèi)皮細(xì)胞胞膜和胞漿中。內(nèi)皮細(xì)胞形成條狀或隙狀等孤立或簇狀結(jié)構(gòu),棕染。按Weinder法并稍加改進(jìn), 在100倍顯微鏡下,確定5個(gè)觀察微血管的密集區(qū),然后在200倍顯微鏡下計(jì)數(shù)每個(gè)密度區(qū)中1個(gè)視野的微血管數(shù)量,無論有無管腔,凡是單個(gè)孤立內(nèi)皮細(xì)胞或多個(gè)內(nèi)皮細(xì)胞緊密排列計(jì)數(shù)為1個(gè)微血管,凡是管腔的面積大于8個(gè)紅細(xì)胞的直徑并帶有較厚肌層的微血管均不計(jì)數(shù)在內(nèi)。以5個(gè)視野區(qū)域微血管數(shù)的均值表示腫瘤的MVD。

1.4 統(tǒng)計(jì)學(xué)分析采用SPSS 17.0軟件進(jìn)行統(tǒng)計(jì)學(xué)處理。CD4及CD8陽性表達(dá)率、CD4與CD8陽性表達(dá)率的比值(CD4/CD8比值)和MVD以±s表示,組間比較采用t檢驗(yàn);CD4陽性表達(dá)率、CD8陽性表達(dá)率和CD4/CD8比值與乳腺癌間質(zhì)MVD的相關(guān)性分析采用Spearman等級(jí)相關(guān)檢驗(yàn)。

2 結(jié)果

2.1 CD4及CD8在乳腺浸潤性導(dǎo)管癌和癌旁組織淋巴細(xì)胞中的表達(dá)CD4及CD8均表達(dá)于腫瘤間質(zhì)T淋巴細(xì)胞的胞膜上,并且呈現(xiàn)在腫瘤間質(zhì)微血管周圍分布較集中的特點(diǎn)。見圖1和2(插頁五和六)。

CD4在乳腺浸潤性導(dǎo)管癌間質(zhì)淋巴細(xì)胞中陽性表達(dá)率為(22.63±11.53)%,與癌旁組織陽性表達(dá)率[(34.09±10.41)%]比較明顯降低(P＜0.05);并且隨著乳腺癌組織學(xué)級(jí)別的升高,CD4陽性表達(dá)率逐漸降低(P＜0.05)。CD8在乳腺浸潤性導(dǎo)管癌間質(zhì)淋巴細(xì)胞中陽性表達(dá)率為(14.27± 9.03)%,與癌旁組織陽性表達(dá)率[(10.51± 1.88)%]比較差異無統(tǒng)計(jì)學(xué)意義(P＞0.05);隨著乳腺癌組織學(xué)級(jí)別的升高,CD8陽性表達(dá)率逐漸升高(P＜0.01)。在癌旁組織及浸潤性導(dǎo)管癌中CD4/CD8比值分別為3.24±1.02及2.16±2.17,二者比較差異無統(tǒng)計(jì)學(xué)意義(P＞0.05);隨著乳腺癌組織學(xué)級(jí)別的升高,其比值降低,差異有統(tǒng)計(jì)學(xué)意義(P＜0.01)。見表1。

2.2 CD34在乳腺浸潤性導(dǎo)管癌和癌旁組織間質(zhì)血管內(nèi)皮細(xì)胞中表達(dá)應(yīng)用抗CD34單克隆抗體,標(biāo)記腫瘤間質(zhì)中微血管內(nèi)皮細(xì)胞(圖3,見插頁六),計(jì)數(shù)MVD。在癌旁組織中MVD為38.47± 5.32,在乳腺浸潤性導(dǎo)管癌Ⅰ、Ⅱ和Ⅲ級(jí)中MVD分別為41.99±8.05、64.04±10.14和79.61± 4.66。乳腺浸潤性導(dǎo)管癌組織中的MVD值明顯高于癌旁組織(P＜0.05),并且隨乳腺癌組織學(xué)級(jí)別的升高,MVD呈遞增趨勢(shì)。

表1 CD4及CD8在乳腺浸潤性導(dǎo)管癌及癌旁組織間質(zhì)淋巴細(xì)胞中的表達(dá)Tab.1 Expressions of CD4 and CD8 in breast invasive ductal carcinoma and adjacent tissues(±s)

表1 CD4及CD8在乳腺浸潤性導(dǎo)管癌及癌旁組織間質(zhì)淋巴細(xì)胞中的表達(dá)Tab.1 Expressions of CD4 and CD8 in breast invasive ductal carcinoma and adjacent tissues(±s)

?P＜0.05 compared with adjacent tissue group;△P＜0.01 compared with gradeⅠgroup.

Group n CD4(η/%)CD8(η/%)CD4/CD8 Adjacent tissue 10 34.09±10.41 10.51±1.88 3.24±1.02 Invasive ductal carcinoma 37 22.63±11.53?14.27±9.03 2.16±2.17 GradeⅠ8 31.81±9.92 7.20±0.65 4.42±1.68 GradeⅡ25 19.70±9.51△17.64±9.65△1.12±1.93△GradeⅢ4 16.38±1.09△17.98±1.59△0.91±0.06△

2.3 CD4陽性表達(dá)率、CD8陽性表達(dá)率及CD4/ CD8比值與乳腺癌組織間質(zhì)MVD的相關(guān)性分析CD4和CD8陽性表達(dá)率、CD4/CD8比值及MVD值均呈非正態(tài)分布。CD4陽性表達(dá)率與MVD呈負(fù)相關(guān)關(guān)系(r＝－1.000,P＜0.001);CD8陽性表達(dá)率與MVD呈正相關(guān)關(guān)系(r＝0.984,P＜0.001);CD4/CD8比值與MVD呈負(fù)相關(guān)關(guān)系(r＝－0.984,P＜0.001)。

3 討論

腫瘤細(xì)胞間質(zhì)中聚集的淋巴細(xì)胞被稱為腫瘤浸潤性淋巴細(xì)胞(tumor infiltrating lymphocytes, TIL),主要包括輔助性T淋巴細(xì)胞(CD4陽性T細(xì)胞)和細(xì)胞毒性T淋巴細(xì)胞(CD8陽性T細(xì)胞)。因其與腫瘤細(xì)胞密切接觸,被認(rèn)為是機(jī)體免疫系統(tǒng)對(duì)腫瘤的直接而又特異的識(shí)別者[6-8]。CD4陽性T細(xì)胞是抗原提呈細(xì)胞,其通過直接或者間接的作用,協(xié)調(diào)B細(xì)胞分化成漿細(xì)胞產(chǎn)生抗體,并且可以激活CD8陽性T細(xì)胞。CD8陽性T細(xì)胞不僅可以通過分泌細(xì)胞因子以提高免疫效應(yīng),也能直接殺傷腫瘤細(xì)胞。CD4和CD8陽性T細(xì)胞共同構(gòu)成免疫調(diào)節(jié)的中心樞紐,二者的平衡承擔(dān)著維持機(jī)體正常免疫應(yīng)答的作用[9-11]。因此在腫瘤微環(huán)境中,浸潤的免疫細(xì)胞的數(shù)量改變及功能變化,在一定程度上反映了機(jī)體抗腫瘤反應(yīng)的狀態(tài)[12-16]。

為了驗(yàn)證CD4和CD8在乳腺癌組織間質(zhì)淋巴細(xì)胞中表達(dá)的變化規(guī)律,本文作者檢測(cè)了37例乳腺癌及癌旁乳腺組織間質(zhì)中CD4和CD8的表達(dá),結(jié)果顯示:CD4在乳腺浸潤性導(dǎo)管癌間質(zhì)淋巴細(xì)胞中的表達(dá)水平明顯低于癌旁組織;并且隨著乳腺癌組織學(xué)級(jí)別的升高,CD4陽性表達(dá)率降低;CD8在乳腺浸潤性導(dǎo)管癌間質(zhì)淋巴細(xì)胞中的表達(dá)率則明顯高于癌旁組織,并隨著乳腺癌組織學(xué)級(jí)別的升高,CD8陽性表達(dá)率升高;分析CD4/CD8比值,結(jié)果顯示:乳腺癌組織CD4/CD8比值低于癌旁組織,但二者比較差異無統(tǒng)計(jì)學(xué)意義,在浸潤性導(dǎo)管癌各級(jí)別之間CD4/CD8比值比較差異有統(tǒng)計(jì)學(xué)意義;Spearman相關(guān)性分析結(jié)果顯示:CD4陽性表達(dá)率與MVD呈負(fù)相關(guān)關(guān)系,而CD8陽性表達(dá)率與MVD呈正相關(guān)關(guān)系,CD4/CD8比值與MVD呈負(fù)相關(guān)關(guān)系。以上研究結(jié)果證實(shí):在乳腺癌惡性進(jìn)展的過程中,CD4陽性T細(xì)胞進(jìn)行性減少,而CD8陽性T細(xì)胞增多,二者的比值明顯下降。CD4/CD8比值能反映機(jī)體的免疫狀態(tài)和抗腫瘤能力[17-18]。然而目前國際上對(duì)于淋巴細(xì)胞亞群以及CD4/CD8比值并未建立統(tǒng)一數(shù)值,尤其腫瘤間質(zhì)浸潤淋巴細(xì)胞中CD4/CD8比值的提示意義尚有待進(jìn)一步研究證實(shí)。有研究[19-20]表明:在惡性腫瘤的演進(jìn)過程中,腫瘤細(xì)胞產(chǎn)生一些免疫抑制因子(IL-10、TGF-β等),抑制淋巴細(xì)胞分化增殖,淋巴細(xì)胞表面CD4細(xì)胞抗原減少,對(duì)CD4陽性T細(xì)胞產(chǎn)生抑制作用,而CD8陽性T細(xì)胞反應(yīng)性增多,通過抑制抗體的合成、分泌,抑制T細(xì)胞的自我增殖。因此,CD4/CD8比值下降使機(jī)體免疫水平處于抑制狀態(tài),容易導(dǎo)致腫瘤轉(zhuǎn)移。本研究中相關(guān)性分析結(jié)果顯示:CD4/CD8比值與MVD呈負(fù)相關(guān)關(guān)系,進(jìn)一步驗(yàn)證腫瘤微環(huán)境中免疫抑制狀態(tài)越明顯,腫瘤間質(zhì)血管新生能力越強(qiáng),但二者之間的潛在調(diào)控關(guān)系有待進(jìn)一步研究證實(shí)。

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?吉林大學(xué)臨床醫(yī)學(xué)專業(yè)5年制2011級(jí)

Correlation of CD4 and CD8 positive lymphocytes with tumor angiogenesis in microenvironment of breast invasive ductal carcinoma

LA Zong1,2,WANG Jian-xia1,CUI Ni?,LI Ming-yue1,XING Shu-gang1,REN Bo1, ZHANG Li-hong1,LI Wei1,LI Yu-lin1
(1.Department of Pathology,School of Basic Medical Sciences,Key Laboratory of Pathobiology, Ministry of Education,Jilin University,Changchun 130021,China;2.Department of Pathology, School of Medical Sciences,University of Tibet,Lasa 850000,China)

breast neoplasms;T lymphocytes;tumor angiogenesis;CD4;CD8

R737.9

A

2014-02-24

吉林省科技廳自然科學(xué)基金資助課題(20130102084JC);吉林大學(xué)白求恩醫(yī)學(xué)科研支持計(jì)劃資助課題(2013101005);吉林大學(xué)“大學(xué)生創(chuàng)新創(chuàng)業(yè)訓(xùn)練計(jì)劃”國家級(jí)項(xiàng)目資助課題(2013A71249)

拉 宗(1975－),女,西藏自治區(qū)拉薩市人,講師,醫(yī)學(xué)碩士,主要從事腫瘤間質(zhì)病理生物學(xué)方面的研究。

李玉林(Tel:0431-85619481,E-mail:ylli＠jlu.edu.cn);

李 偉(Tel:0431-85619481,E-mail:liwei2006＠jlu.edu.cn)

時(shí)間: 2014-08-27 14:41

網(wǎng)絡(luò)出版地址: http://www.cnki.net/kcms/detail/22.1342.R.20140827.1441.002.html

1671-587Ⅹ(2014)05-1069-05

10.13481/j.1671-587x.20140531

Abstract:Objective To detect the percentages of CD4＋,CD8＋T lymphocytes in the breast invasive ductal carcinoma microenvironment,and to analyze their correlation with breast carcinoma microvessel density(MVD).MethodsThe expressions of CD4,CD8 and CD34 were detected in 10 cases of adjacent normal breast tissue and 37 cases of breast invasive ductal carcinoma tissue by immunohistochemistry.The correlations between CD4,CD8, CD4/CD8 and MVD were analyzed by Spearman correlation analysis.ResultsThe CD4 expression level (22.63%±11.53%)in breast invasive ductal carcinoma tissue was lower than that in adjacent tissue(34.09%± 10.41%),and there was statistically significant difference(P＜0.05).With the increasing of the histological grade of breast cancer,grade,the expression level of CD4 was gradually decreased(P＜0.05).The CD8 expression level (14.27%±9.03%)in breast invasive ductal carcinoma tissue was higher than that in adjacent tissue(10.51%± 1.88%),but there was no statistically significant difference(P＞0.05).With the increasing of the histological grade of breast cancer,the expression level of CD8 was gradually increased(P＜0.01).The CD4/CD8 ratios in adjacent tissue group and breast invasive ductal carcinoma tissue group were 3.24±1.02 and 2.16±2.17,and there was no statistically significant difference between them(P＞0.05).With the increasing of histological grade of breast invasive ductal carcinoma,the CD4/CD8 ratios were decreased(P＜0.01).The MVD in breast invasive ductal carcinoma tissue was obviously higher than that in adjacent tissue,and it showed an increasing trend with the increasing of the histological grade of breast invasive ductal carcinoma(P＜0.05).The correlation analysis showed that the MVD was negatively correlated with the CD4 expression(r＝－1.000,P＜0.001)as well as CD4/CD8 ratio(r＝－0.984,P＜0.001),and was positively correlated with the CD8 expression level(r＝0.984,P＜0.001).ConclusionThe expression of CD4 is decreased in breast cancer tissue,the expression of CD8 is elevated, and the CD4/CD8 ratio is decreased,which suggests that T cells in the breast cancer microenvironment are immunosuppressed.