調(diào)節(jié)性T細(xì)胞介導(dǎo)的免疫逃逸在腫瘤中的作用

1、調(diào)節(jié)性T細(xì)胞(Treg)介導(dǎo)的免疫逃逸在腫瘤中的作用調(diào)節(jié)性T細(xì)胞(regulatory T cells, Treg)是一群具有免疫抑制功能的T細(xì) 胞，主要包括天然型Treg(CD4+CD25+Treg)和誘導(dǎo)型Treg(iTreg)兩大 類。Treg在慢性免疫應(yīng)答中可以限制自身免疫造成的組織損傷，但卻給腫瘤逃 避機(jī)體的免疫創(chuàng)造了條件。Treg能夠通過(guò)以下多種途徑抑制機(jī)體免疫反應(yīng)，促 使腫瘤細(xì)胞發(fā)生免疫耐受逃逸：(1)Treg通過(guò)分泌多種抑制性細(xì)胞因子，如 TGF-B、IL-10、IL-35等，發(fā)揮免疫抑制效應(yīng)1； (2) Treg表面組成性表達(dá)CD25 (IL2Ra鏈)，能與效應(yīng)T細(xì)胞競(jìng)爭(zhēng)性結(jié)

2、合并大量消耗IL-2，從而抑制效應(yīng)細(xì)胞 (如CD4+和CD8+T淋巴細(xì)胞)的增殖2； (3) Treg表面組成性表達(dá)CTLA-4, 能與樹(shù)突細(xì)胞(DC)表面配體CD80和CD86相互作用，從而阻斷它們的共刺 激功能和隨后的T細(xì)胞活化和功能3； (4)在腫瘤微環(huán)境中Treg可以表達(dá)顆粒 酶B,以顆粒酶B/穿孔素依賴的方式使NK、CTL等細(xì)胞溶解，抑制機(jī)體抗腫 瘤免疫4。iTreg細(xì)胞由多種成分在外周誘導(dǎo)產(chǎn)生，主要以細(xì)胞因子依賴(IL-10和 TGF-B )發(fā)揮免疫負(fù)調(diào)節(jié)作用。CD4+CD25+Treg特異性表達(dá)轉(zhuǎn)錄因子FOXP3,FOXP3在Treg的分化發(fā) 育及其介導(dǎo)的腫瘤免疫逃逸中發(fā)揮關(guān)鍵作

3、用，因而是鑒別腫瘤微環(huán)境中Treg的 有效靶標(biāo)5。越來(lái)越多的研究表明Treg介導(dǎo)的免疫監(jiān)視逃逸在腫瘤的發(fā)生發(fā)展 過(guò)程中發(fā)揮著重要作用。Treg已被發(fā)現(xiàn)在腫瘤患者外周血和腫瘤組織中過(guò)量增 加，包括乳腺癌6、腸癌7、胃癌8、白血病9、黑色素瘤10、非小細(xì)胞肺癌11、卵 巢癌12和肝癌13。大多數(shù)證據(jù)表明腫瘤微環(huán)境中Treg高表達(dá)和預(yù)后不良有關(guān)。 然而，Treg浸潤(rùn)到腫瘤內(nèi)部和周圍卻沒(méi)有顯著作用，甚至是對(duì)患者有益的，這 可能和腫瘤類型，Treg分布和定位有關(guān)。如Fridman等研究發(fā)現(xiàn)，結(jié)直腸癌患 者腫瘤組織浸潤(rùn)高密度的FOXP3+Treg細(xì)胞提示患者的預(yù)后較好14。盡管如此， 目前人們普遍認(rèn)為Tr

4、eg浸潤(rùn)的腫瘤抑制免疫干預(yù)的療效，因而成為腫瘤免疫治 療的新方向。如抗CTLA-4單抗，在II期臨床試驗(yàn)中能有效延長(zhǎng)IV期黑色素瘤 患者的存活時(shí)間。能夠阻斷體外CCL22-介導(dǎo)的Treg和Th2招募過(guò)程的小分子 趨化因子受體拮抗劑或單抗也已進(jìn)入I期臨床試驗(yàn)階段15。最近一些研究為Treg的免疫抑制功能提供了新的機(jī)制。Vizio等發(fā)現(xiàn)FoxP3+Treg細(xì)胞參與Th17啟動(dòng)的癌變過(guò)程16。Treg抑制宮頸癌腫瘤微環(huán)境中 存在的腫瘤浸潤(rùn)Th1和Th2效應(yīng)分子17。此外，F(xiàn)OXP3 +調(diào)節(jié)性T細(xì)胞包括不同 亞群，其中CXCR3+ Treg細(xì)胞，已被證明特異性地控制體內(nèi)的I型T細(xì)胞反應(yīng)。 Redjim

5、i等發(fā)現(xiàn)CXCR3+ Treg細(xì)胞高度富集于人類卵巢癌，特別是在實(shí)體腫瘤 中，控制I型T細(xì)胞應(yīng)答，導(dǎo)致免疫抑制18。綜上，關(guān)于Treg細(xì)胞與腫瘤的關(guān)系以及作用機(jī)制有待深入研究，為腫瘤的 免疫治療提供更多新的思路，從而為腫瘤的治療帶來(lái)新的突破。參考文獻(xiàn)Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL. A unique subset of CD4+CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth facto

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