國(guó)自然調(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 要分為天然型Treg（CD4+CD25+Treg）和誘導(dǎo)型Treg（iTreg）兩大類(lèi)。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，但卻也給腫瘤逃避機(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-8、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)合

2、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(lài) 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(lài)（IL-10和TGF-p ）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)鍵作用，因而

3、是鑒別腫瘤微環(huán)境中Treg的有效靶標(biāo)5。預(yù)防性Foxp3 DNA /重組蛋白疫苗（Foxp3疫苗）在無(wú)腫瘤條件下促進(jìn)針對(duì)Treg的免疫性，通過(guò)靶向Treg和 MDSC來(lái)促進(jìn)針對(duì)腫瘤的免疫應(yīng)答，這可以被用作潛在的免疫治療方法6。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7, 8。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9、腸癌10、胃癌11、白血病12、黑色 素瘤13、非小細(xì)胞肺癌14、卵巢癌15和肝癌16。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 F

4、OXP3+Treg細(xì)胞提示患者的預(yù)后較好直，這可能是和腫瘤類(lèi)型、Treg的分布和定位有關(guān)。 盡管如此，目前人們普遍認(rèn)為活的Treg細(xì)胞抑制抗腫瘤免疫18，因而它成為了腫瘤免疫治 療的新方向。如，有研究發(fā)現(xiàn)后萎縮性增生（PAH）在CD4 + Tregs存在下直接進(jìn)入前列腺 癌的可能途徑，并且表明即使在原發(fā)性腫瘤建立之前，抗腫瘤免疫應(yīng)答的轉(zhuǎn)化也可能開(kāi)始19。 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20。在腎細(xì)胞癌中，由新的肽拮抗劑肽-R29引發(fā)的

5、CXCR4拮抗作用能有效地逆 轉(zhuǎn)Teff增殖的Treg抑制，這可能是腫瘤免疫應(yīng)答的可靠生物標(biāo)志物21。最近一些研究為T(mén)reg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22。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23。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)。Redjimi等發(fā)現(xiàn)CXCR3+ Treg細(xì)胞高度富集于人類(lèi)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24。HIV感染誘導(dǎo)CD8 + CD28-CD127l

6、oCD39 + Treg細(xì)胞的顯著擴(kuò)增，其頻率與臨床疾病和慢性免疫細(xì)胞活化的跡象 相關(guān)25。綜上，關(guān)于Treg細(xì)胞與腫瘤的關(guān)系以及作用機(jī)制還有待深入的研究，以此為腫瘤的免 疫治療提供更多新的思路，為腫瘤的治療帶來(lái)新的突破。參考文獻(xiàn)Kanamori M, Nakatsukasa H, Okada M, Lu Q, Yoshimura A. Induced Regulatory T Cells: Their Development, Stability, and Applications. Trends in immunology2016.Sakaguchi S, Miyara M, Costan

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