李艷雙　楊麗娟

華北理工大學(xué)臨床醫(yī)學(xué)院　河北唐山　063000；①河北醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院

腫瘤微環(huán)境中淋巴細(xì)胞的種類與功能研究進(jìn)展

李艷雙楊麗娟①

華北理工大學(xué)臨床醫(yī)學(xué)院河北唐山063000；①河北醫(yī)科大學(xué)基礎(chǔ)醫(yī)學(xué)院

[關(guān)鍵詞]淋巴細(xì)胞微環(huán)境腫瘤

腫瘤微環(huán)境是腫瘤細(xì)胞生存的空間，是由許多因素交織在一起的復(fù)雜的微小環(huán)境，包括多種細(xì)胞及其分泌的各類因子。這些細(xì)胞和因子彼此之間相互作用，使腫瘤微環(huán)境向著有利于腫瘤生長的趨勢發(fā)展[1]，其中淋巴細(xì)胞即參與了這種趨勢的形成[2]。腫瘤浸潤的淋巴細(xì)胞并沒有發(fā)揮其相應(yīng)的免疫功能，而是在腫瘤微環(huán)境的壓力下，對腫瘤細(xì)胞的生長及其免疫逃逸起了促進(jìn)作用[3]。而且浸潤淋巴細(xì)胞的類別與腫瘤的生長大小及其預(yù)后、復(fù)發(fā)和轉(zhuǎn)移有密切關(guān)系[4]。

淋巴細(xì)胞可以分為T淋巴細(xì)胞和B淋巴細(xì)胞，成熟的T淋巴細(xì)胞依據(jù)其細(xì)胞表面是否表達(dá)CD4或CD8分子可以分為CD4+和CD8+T淋巴細(xì)胞。CD4+效應(yīng)T細(xì)胞依據(jù)其分泌的細(xì)胞因子的不同，又可進(jìn)一步分為Th1細(xì)胞、Th2細(xì)胞、Th17細(xì)胞、Treg細(xì)胞等?，F(xiàn)對其在腫瘤發(fā)生發(fā)展中的作用及在腫瘤微環(huán)境中的浸潤情況以及生物學(xué)功能綜述如下。

1Th1/ Th2淋巴細(xì)胞

Th1細(xì)胞主要分泌細(xì)胞因子白細(xì)胞介素(IL)-2、干擾素(IFN)-γ等，介導(dǎo)與局部炎癥相關(guān)的免疫應(yīng)答，而且可以活化CD8+的T淋巴細(xì)胞和自然殺傷細(xì)胞(NK)，參與細(xì)胞免疫應(yīng)答。IFN-γ在Th1細(xì)胞調(diào)節(jié)功能中起關(guān)鍵作用，亦可維持Th1細(xì)胞表型的穩(wěn)定性[5]。而Th2細(xì)胞主要分泌IL-4、IL-6、IL-10等細(xì)胞因子，在體液免疫中起關(guān)鍵作用。Th1和Th2細(xì)胞及其分泌的細(xì)胞因子之間有一定的關(guān)聯(lián)性。Th1細(xì)胞分泌的細(xì)胞因子IFN-γ可以誘導(dǎo)Th1細(xì)胞的分化，但卻降低Th2細(xì)胞的分化和增殖，使IL-4等細(xì)胞因子分泌減少。而相反Th2細(xì)胞分泌的細(xì)胞因子IL-4可誘導(dǎo)Th2細(xì)胞的分化增殖，但能減少Th1細(xì)胞分泌IFN-γ。Th1和Th2細(xì)胞不僅在免疫應(yīng)答中起關(guān)鍵作用，在腫瘤微環(huán)境中，對腫瘤的發(fā)生發(fā)展也起到不可或缺的作用。已有證據(jù)表明，IFN-γ具有抗腫瘤免疫應(yīng)答的作用[6]。而Th2細(xì)胞及其分泌的細(xì)胞因子可以通過活化巨噬細(xì)胞及髓源抑制細(xì)胞參與腫瘤的發(fā)生發(fā)展過程[7,8]， Th2細(xì)胞及其細(xì)胞因子是否促進(jìn)了腫瘤的發(fā)生發(fā)展，還有待進(jìn)一步證明。

2Th17細(xì)胞

除了Th1和Th2細(xì)胞外，還發(fā)現(xiàn)一類效應(yīng)T細(xì)胞的亞群，即Th17細(xì)胞亞群。Th17細(xì)胞是效應(yīng)T細(xì)胞中最早參與抗感染應(yīng)答的細(xì)胞。不僅許多細(xì)胞因子和轉(zhuǎn)錄因子可以調(diào)節(jié)Th17細(xì)胞的增長，如IL-6、轉(zhuǎn)化生長因子(TGF)-β、RAR相關(guān)孤兒受體(ROR-γt)等[9]，而且Th17細(xì)胞本身也可以分泌許多細(xì)胞因子，如IL-17、IL-21、IL-22等。其中IL-17是一種促炎因子，不僅可以活化粒細(xì)胞和單核細(xì)胞，還可以誘導(dǎo)上皮細(xì)胞分泌趨化因子以及促進(jìn)其他炎性因子和前列腺素的分泌[10]。

Th17細(xì)胞及其分泌的細(xì)胞因子除了參與抗感染免疫應(yīng)答外，與腫瘤的發(fā)生發(fā)展及預(yù)后也有極其密切的關(guān)系。首先，與健康機(jī)體相比，多種腫瘤患者的外周血和腫瘤組織中Th17細(xì)胞的比例是有變化的。Th17細(xì)胞僅占健康人循環(huán)CD4+T細(xì)胞的少數(shù)[11,12]。與正常人相比，胃癌患者的外周血中Th17細(xì)胞的比例升高[13]。在鼠的上頜面腫瘤、纖維肉瘤、前列腺癌的模型中，也可以檢測到比例升高的Th17細(xì)胞[14]。有研究發(fā)現(xiàn)，人類多種惡性腫瘤中，浸潤的T淋巴細(xì)胞，Th17細(xì)胞的比例較相鄰的組織是顯著升高的，例如，肝細(xì)胞癌[15]、頭頸部鱗狀細(xì)胞癌[16]、乳腺癌[17]、胰腺癌[18]。然而，盡管卵巢癌患者腫瘤組織中Th17細(xì)胞的比例較正常人顯著升高，但是其外周血中Th17細(xì)胞的比例并沒有明顯的變化[19]。

上述說明腫瘤患者外周血及腫瘤組織中Th17細(xì)胞的數(shù)量與正常人相比有變化，但Th17細(xì)胞對腫瘤發(fā)生發(fā)展的作用尚有爭議[20]。許多證據(jù)表明，在腫瘤微環(huán)境中，Th17細(xì)胞起抗腫瘤效應(yīng)。有研究表明Th17細(xì)胞有較好的抗腫瘤作用，特別是其與IFN-γ、Th1細(xì)胞或活化的CD8+T細(xì)胞共同存在時(shí)[21～23]。Th17細(xì)胞可以通過刺激趨化因子(CXCL)9、10的生成來招募效應(yīng)T細(xì)胞，這些效應(yīng)T細(xì)胞在抗腫瘤免疫應(yīng)答中起積極的作用[24]。Th17細(xì)胞分泌的細(xì)胞因子IL-17高表達(dá)對腫瘤的生存期也起到正面作用[17]。但是，相反的發(fā)現(xiàn)在腫瘤微環(huán)境中，Th17細(xì)胞可以促進(jìn)腫瘤的發(fā)展[25,26]，而IL-17也有促進(jìn)腫瘤生長的作用[27]。有研究表明，IL-17高表達(dá)與腫瘤的微血管密度、不良預(yù)后和低生存期有關(guān)系[28,29]。同樣，在黑色素瘤中，IL-17可以通過與其他細(xì)胞因子作用而促進(jìn)腫瘤血管的發(fā)生[20]。

綜上所述，Th17細(xì)胞在腫瘤微環(huán)境中既有抗腫瘤作用，又有促進(jìn)腫瘤生長的作用，這也許與其數(shù)量及其在腫瘤微環(huán)境中的特性和腫瘤的階段有關(guān)。

3Treg細(xì)胞

Treg細(xì)胞是另一種CD4+T細(xì)胞亞群，具有明顯的免疫抑制作用，可通過不同的途徑對機(jī)體的免疫應(yīng)答進(jìn)行負(fù)調(diào)節(jié)作用?？梢砸种芅K細(xì)胞的活性及CD8+T細(xì)胞的溶細(xì)胞功能[9,30]。Treg細(xì)胞也可以分泌多種細(xì)胞因子及轉(zhuǎn)錄因子，例如IL-10、TGF-β、Foxp3等。其中Treg細(xì)胞的特征性轉(zhuǎn)錄因子是Foxp3[31]。作為Treg細(xì)胞的關(guān)鍵的轉(zhuǎn)錄調(diào)節(jié)因子，F(xiàn)oxp3可以抑制炎性因子的表達(dá)，并可以促進(jìn)Treg細(xì)胞的相關(guān)基因的表達(dá)[32]。Treg細(xì)胞不僅可以抑制宿主的免疫應(yīng)答，而且在對腫瘤抗原的免疫應(yīng)答的調(diào)節(jié)中也起到重要的作用[33,34]。另外腫瘤細(xì)胞可以招募Treg細(xì)胞到腫瘤的微環(huán)境中去。許多研究證明，多種腫瘤患者外周血中及腫瘤組織中分離出的Treg細(xì)胞占總T細(xì)胞的比例升高，如卵巢癌[35]、黑色素瘤[36]、肝癌[37]、胃癌[38]、淋巴瘤[39]、宮頸癌[40]。Treg細(xì)胞在腫瘤微環(huán)境中的比例增加，抑制了機(jī)體對腫瘤細(xì)胞的抗腫瘤免疫應(yīng)答，而且可以誘導(dǎo)腫瘤局部的免疫耐受，從而限制了免疫療法的抗癌療效。有研究表明，腫瘤浸潤的Treg細(xì)胞可以抑制初始T細(xì)胞的增殖[41]，在卵巢癌中，Treg細(xì)胞的比例升高與癌癥患者的不良預(yù)后緊密關(guān)聯(lián)[35]。在宮頸癌中發(fā)現(xiàn)，Treg細(xì)胞出現(xiàn)的頻率與腫瘤的分化程度有關(guān)，腫瘤分化程度越低，Treg細(xì)胞出現(xiàn)的頻率越高[42]。以上這些表明Treg細(xì)胞在腫瘤微環(huán)境中可以抑制機(jī)體的抗腫瘤免疫應(yīng)答，從而促進(jìn)腫瘤的生長。

Th17細(xì)胞和Treg細(xì)胞及其分泌的細(xì)胞因子之間也存在一定的關(guān)系，從而影響腫瘤的發(fā)生發(fā)展。有研究表明在前列腺癌的腫瘤組織中，腫瘤浸潤的T淋巴細(xì)胞主要是Th17細(xì)胞和Treg細(xì)胞[25]。而Treg細(xì)胞相關(guān)的轉(zhuǎn)錄因子TGF-β可以誘導(dǎo)Th17細(xì)胞表達(dá)外核苷酸酶，從而釋放免疫抑制腺苷。而當(dāng)TGF-β與IL-6共同存在時(shí)，Th17細(xì)胞可以通過釋放抑制性的細(xì)胞因子IL-10從而行使其調(diào)節(jié)功能。而且Th17細(xì)胞因其可塑性可逐漸轉(zhuǎn)變?yōu)門reg細(xì)胞，這種轉(zhuǎn)變或許與T細(xì)胞抗原受體有關(guān)。

4CTL細(xì)胞

除了對以上幾種淋巴細(xì)胞的研究外，對CTL細(xì)胞也有相關(guān)的研究。CTL有CD4+CTL和CD8+CTL，其中CD8+CTL是機(jī)體發(fā)揮細(xì)胞毒作用的主要效應(yīng)細(xì)胞。CTL也會影響腫瘤的生長。在乳腺癌的腫瘤微環(huán)境中可檢測到大量的CTL， CTL能夠通過分泌穿孔蛋白以及顆粒霉素B而使腫瘤細(xì)胞發(fā)生溶解，F(xiàn)asLCTL還可以通過Fas/ FasL途徑而誘導(dǎo)腫瘤細(xì)胞凋亡。因此CTL對腫瘤細(xì)胞具有殺傷作用，但是某些腫瘤細(xì)胞可以通過使Fas表達(dá)下調(diào)或FasL的表達(dá)增加，從而逃避免疫細(xì)胞的攻擊。而且腫瘤特異性的CTL的增殖及其細(xì)胞毒作用可以被Treg抑制[42]，從而降低了CTL對腫瘤細(xì)胞的殺傷效應(yīng)。

5小結(jié)

綜上所述，腫瘤微環(huán)境中浸潤的淋巴細(xì)胞并不是都會產(chǎn)生抑瘤效應(yīng)，而是因其種類、數(shù)量及其功能不同，對腫瘤的發(fā)生發(fā)展、預(yù)后及其生存期有著不同的作用。而且一種淋巴細(xì)胞通過不同的途徑機(jī)制既可以抑制腫瘤的生長，也可以促進(jìn)腫瘤的生長；且一種淋巴細(xì)胞的作用可能會被另外的淋巴細(xì)胞或細(xì)胞因子抑制。在復(fù)雜的腫瘤微環(huán)境中淋巴細(xì)胞不只是參與其中，而是淋巴細(xì)胞與淋巴細(xì)胞之間，以及與其他細(xì)胞和細(xì)胞因子之間都有著復(fù)雜的作用關(guān)系。因此對腫瘤微環(huán)境中的淋巴細(xì)胞還需要進(jìn)一步深入研究，為腫瘤的治療提供更多的新思路、新靶點(diǎn)、新方法。

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(2015-09-26收稿)(張愛國編輯)

【作者簡介】李艷雙(1985-)，女，碩士，助教。研究方向：腫瘤免疫。

【通訊作者】楊麗娟。

[中圖分類號]R 392.12

[文獻(xiàn)標(biāo)識碼]A

[文章編號]2095-2694(2016)03-245-05