時林森， 沙索友， 邵永， 朱孝成

作者單位： 221006 江蘇 徐州，徐州醫(yī)科大學(xué)附屬醫(yī)院 胃腸外科

綜述與講座

腺苷、調(diào)節(jié)性T細(xì)胞在胃癌的免疫調(diào)控中的進(jìn)展

時林森， 沙索友， 邵永， 朱孝成

腫瘤免疫治療是一種有效的手段。調(diào)節(jié)性T細(xì)胞(Treg)可通過細(xì)胞表面外核苷酸酶(CD39，CD73)降解ATP生成腺苷(ADO)，ADO和細(xì)胞表面A2aR結(jié)合后可激活細(xì)胞內(nèi)腺苷酸環(huán)化酶合成cAMP，從而進(jìn)一步抑制效應(yīng)T細(xì)胞(Teff)的免疫活性。胃癌作為常見的消化道惡性腫瘤之一，其免疫治療尚處于臨床前期或起步階段。近年來，關(guān)于腺苷在調(diào)節(jié)性T細(xì)胞對胃癌免疫調(diào)控中的作用日益受到重視，作者對腺苷、T細(xì)胞與胃癌的研究進(jìn)展進(jìn)行了綜述。

胃腫瘤； 腺苷； T淋巴細(xì)胞,調(diào)節(jié)性； 免疫

腫瘤免疫治療是繼手術(shù)、放療、化療后又一有效治療手段，更是被2013年Science雜志列為當(dāng)年十大科學(xué)突破之首[1]。胃癌作為我國最常見的消化道惡性腫瘤之一，其免疫治療尚處于臨床前期或起步階段[2]。深入研究腫瘤微環(huán)境中復(fù)雜的作用機(jī)制，是腫瘤免疫治療的基礎(chǔ)[3]。近年來，關(guān)于腺苷(adenosine，ADO)在調(diào)節(jié)性T細(xì)胞(Treg)對胃癌免疫調(diào)控中的作用日益受到重視，現(xiàn)對ADO、Treg與胃癌的研究進(jìn)展做一概述。

1 腺苷受體家族

ADO是機(jī)體ATP代謝產(chǎn)物，細(xì)胞內(nèi)ADO參與細(xì)胞的能量代謝、核算合成等生理過程，而在細(xì)胞外則是重要的信號傳導(dǎo)因子。正常生理狀態(tài)下，ADO的生成和細(xì)胞攝取及降解保持動態(tài)平衡。在炎癥及腫瘤組織缺氧條件下，ATP不充分裂解，低氧誘導(dǎo)因子-α(HIF-α)誘導(dǎo)組織外核苷酸酶(CD39、CD73)的過表達(dá)，使組織ADO水平明顯升高。在腫瘤微環(huán)境中，其不僅可以抑制免疫殺傷細(xì)胞的抗腫瘤免疫應(yīng)答，而且可以促進(jìn)免疫抑制細(xì)胞的極化和增殖，有利于腫瘤新生血管形成，從而促進(jìn)腫瘤生長(圖1)[4]。

ADO受體的生理作用主要是通過與其受體結(jié)合實現(xiàn)的[5]。其屬于G蛋白偶聯(lián)受體超家族，共有7個跨膜結(jié)構(gòu)域，與胞內(nèi)GTP結(jié)合蛋白相偶聯(lián)，共有A1R、A2aR、A2bR及A3R四種腺苷受體(adenosine receptors，ARs)[6]。ARs幾乎在機(jī)體所有細(xì)胞均有表達(dá)，但不同組織及器官其功能各異[7]。其中A2aR與ADO的親和力最強(qiáng)，ADO可通過直接結(jié)合Teff表面A2aR激活細(xì)胞內(nèi)腺苷酸環(huán)化酶生成cAMP或結(jié)合Treg表面A2aR生成cAMP，然后通過細(xì)胞縫隙連接進(jìn)入Teff。阻斷或基因敲除A2aR可明顯降低T細(xì)胞內(nèi)cAMP濃度，小鼠體內(nèi)淋巴瘤和黑素瘤的生長明顯受到抑制[8]。由于缺血、缺氧、炎癥等因素影響，ARs的表達(dá)會明顯上調(diào)[9]。

2 Treg與腫瘤免疫調(diào)控

Treg作為CD4+T細(xì)胞的亞群之一，約占人體外周血CD4+T細(xì)胞總數(shù)的5%，根據(jù)其起源及作用機(jī)制又分為中心性Treg(nTreg)和外周性Treg(iTreg)[10]。在健康個體中，nTreg可維持機(jī)體的免疫耐受和免疫平衡，疾病狀態(tài)下iTreg則替代nTreg對外來應(yīng)激作出功能改變并調(diào)控Teff產(chǎn)生免疫反應(yīng)[11]。Treg對機(jī)體免疫應(yīng)答的調(diào)控主要通過以下途徑來實現(xiàn)：①通過產(chǎn)生細(xì)胞因子IL-10，IL-35、轉(zhuǎn)移生長因子-β(TGF-β)等來調(diào)控；②裂解抗原提呈細(xì)胞(APCs)和Teff；③通過細(xì)胞毒T淋巴抗原-4(CTLA-4)和凋亡受體-1(PD-1)介導(dǎo)的細(xì)胞接觸反應(yīng)抑制機(jī)體炎癥反應(yīng)[12-13]。其在機(jī)體的移植免疫耐受、炎癥反應(yīng)、自身免疫性疾病中起著重要的作用[14-15]。Treg與其他T細(xì)胞亞群相比，外核苷酸酶(CD39、CD73)的表達(dá)明顯升高，CD39可降解ATP/ADP生成AMP，CD73可裂解AMP進(jìn)一步生成ADO激活Treg細(xì)胞的抑制活性[16]。CD39、CD73在多種免疫細(xì)胞Treg、CD8+T細(xì)胞、B細(xì)胞均高表達(dá)[17-19]，而腫瘤細(xì)胞表面CD73的表達(dá)和預(yù)后存在相關(guān)性[20-23]?；蚯贸鼵D73后，小鼠體內(nèi)結(jié)腸癌、淋巴瘤、乳腺癌、黑素瘤的生長和轉(zhuǎn)移明顯受到抑制[24-25]。

圖1 ADO、Treg與腫瘤免疫調(diào)控腫瘤缺氧微環(huán)境中HIF-α誘導(dǎo)外核苷酸酶(CD39，CD73)表達(dá)，使組織ADO水平明顯升高。ADO可通過直接結(jié)合Teff表面A2aR激活細(xì)胞內(nèi)腺苷酸環(huán)化酶生成cAMP或結(jié)合Treg表面A2aR生成cAMP，然后通過細(xì)胞縫隙連接進(jìn)入Teff。通過減少促炎性細(xì)胞因子IFN-γ、TNF-α、IL-6表達(dá)，增加炎癥抑制因子TGF-β、IL-10等合成；上調(diào)免疫關(guān)鍵節(jié)點受體PD-1，LAG-3的表達(dá)；誘導(dǎo)Treg細(xì)胞分化從而抑制Teff活性

3 腺苷與免疫效應(yīng)細(xì)胞

在缺氧和ADO富集的腫瘤微環(huán)境中，ADO主要通過免疫細(xì)胞表面廣泛表達(dá)的腺苷受體尤其是A2aR來抑制免疫效應(yīng)細(xì)胞，如CD8+T細(xì)胞、NK細(xì)胞、NKT細(xì)胞、樹突細(xì)胞、巨噬細(xì)胞等的功能[17，26-27]。cAMP作為細(xì)胞內(nèi)第二信使，可通過cAMP蛋白激酶-A(PKA)淋巴細(xì)胞特異性絡(luò)氨酸激酶(Lck)/肉瘤基因蛋白激酶(Src激酶)途徑來抑制機(jī)體免疫應(yīng)答[28]。ADO和細(xì)胞表面A2aR結(jié)合后可激活細(xì)胞內(nèi)腺苷酸環(huán)化酶合成cAMP[29]，cAMP通過活化PKA介導(dǎo)的磷酸化又可激活Lck和Src激酶[30]。而Lck和Src激酶的免疫抑制主要通過以下途徑實現(xiàn)：①減少促炎性細(xì)胞因子干擾素-γ、腫瘤壞死因子-α、IL-6表達(dá)，炎癥抑制因子轉(zhuǎn)化生長因子-β、IL-10等合成增加；②上調(diào)免疫關(guān)鍵節(jié)點受體PD-1，LAG-3的表達(dá)；③誘導(dǎo)Treg細(xì)胞分化從而抑制Teff活性[31]。使用A2aR激動劑可明顯抑制T細(xì)胞和NK細(xì)胞免疫功能，這種抑制功能在去除A2aR激動劑仍然持續(xù)存在[32]。Cekic等[33]研究發(fā)現(xiàn)，A2aR缺失的T細(xì)胞雖可明顯增強(qiáng)其抗腫瘤活性，但卻導(dǎo)致T細(xì)胞的半衰期明顯縮短，而過早凋亡的T細(xì)胞又可導(dǎo)致腫瘤的復(fù)發(fā)和進(jìn)展。

4 腺苷與胃癌調(diào)控

胃癌的發(fā)生是一個多因素、多步驟、復(fù)雜的生理病理過程，具體發(fā)生機(jī)制尚不清楚。但大量致癌物，如蒽環(huán)類、亞硝酸鹽、H.pylori感染導(dǎo)致的胃黏膜慢性炎癥及癌前病變是其主要原因，而腫瘤細(xì)胞的免疫逃避則是其中重要的一環(huán)[34]。H.pylori感染和75%的胃癌發(fā)生存在相關(guān)性，其感染胃黏膜細(xì)胞后，Treg可抑制胃黏膜CD4+細(xì)胞的免疫應(yīng)答，導(dǎo)致胃黏膜炎癥和潰瘍形成，同時胃癌細(xì)胞可通過轉(zhuǎn)化生長因子-β誘導(dǎo)Treg分化增殖[35-37]。但是在腫瘤發(fā)生后，Treg抑制宿主的免疫應(yīng)答則會促進(jìn)腫瘤的進(jìn)展和轉(zhuǎn)移[38-40]。胃癌患者外周血和腫瘤組織中，Treg的比例較非腫瘤個體明顯升高[41-43]，而在接受根治性手術(shù)后2個月，其比值降至正常。關(guān)于Treg和胃癌預(yù)后的關(guān)系目前尚有爭議，Kono等[44]認(rèn)為，胃癌患者外周血Treg比例隨著胃癌進(jìn)展而逐漸降低，因此，Treg比例和胃癌患者預(yù)后存在負(fù)相關(guān)[44]。而Haas等[45]的研究則表明，胃癌組織中較高的Treg浸潤程度和胃癌患者術(shù)后生存之間呈正比[45]。國內(nèi)已有學(xué)者證實Treg可通過CD8+T細(xì)胞調(diào)控胃癌細(xì)胞生長[46]。

由于胃癌生理病理的多樣性及機(jī)體免疫調(diào)控網(wǎng)絡(luò)的復(fù)雜性，目前關(guān)于Treg對胃癌免疫調(diào)控的具體機(jī)制尚不十分清楚，腺苷及其受體是否參與了Treg導(dǎo)致腫瘤免疫效應(yīng)細(xì)胞(CD8+T細(xì)胞、NK細(xì)胞等)失活的具體過程目前知之甚少。?ztürk等[47]的研究證實，水飛薊賓提取物可激活胃癌組織中腺苷脫氨酶，從而起到治療胃癌的效果。

5 胃癌免疫治療現(xiàn)狀及展望

腫瘤的免疫治療近年來取得了飛速進(jìn)展，針對關(guān)鍵節(jié)點受體抑制劑、嵌合抗原的T細(xì)胞受體療法、腫瘤浸潤淋巴細(xì)胞過繼療法等免疫治療方法在腫瘤的治療中已經(jīng)有了一定療效[48-51]，但大都存在反應(yīng)率低、療效不確切等缺點。ADO及其受體在腫瘤免疫逃避中發(fā)揮重要作用，針對CD73、A2aR的免疫治療在乳腺癌等腫瘤的臨床前期實驗中已取得了積極結(jié)果[25，52-54]。胃癌作為一種免疫原性較弱的惡性腫瘤，如何選擇合適的治療人群和恰當(dāng)?shù)闹委熓侄问敲庖咧委煶晒Φ年P(guān)鍵。胃癌的基因組圖譜分型為其免疫治療提供了新的視角。根據(jù)分型，胃癌可分為EB病毒陽性型、微衛(wèi)星不穩(wěn)定型、基因穩(wěn)定型和染色體不穩(wěn)定型[55]。其中EB病毒陽性型已證實和PD-L1/2高表達(dá)相關(guān)，亦有臨床試驗證實，微衛(wèi)星不穩(wěn)定型中的超突變亞型對免疫治療療效較好[56]。因此，胃癌的免疫治療下一步將著眼于：①胃癌的免疫調(diào)控機(jī)制和基因分型之間有何關(guān)系？②如何根據(jù)胃癌的基因分型選擇特異性的免疫治療手段？③免疫治療和胃癌的現(xiàn)有治療，如化療、分子靶向藥物、甚至是免疫治療藥物自身之間的聯(lián)合能否提高胃癌治療的有效率？

鑒于ADO及其受體、Treg在腫瘤免疫調(diào)控中處于重要位置，而在胃癌發(fā)生、轉(zhuǎn)移、復(fù)發(fā)的免疫逃避方面仍有大量未知領(lǐng)域和探索空間。因此進(jìn)一步闡明ADO、Treg在胃癌免疫耐受中的作用機(jī)制，有望為胃癌的免疫治療提供新的靶點和更有效途徑，也為晚期、常規(guī)治療療效欠佳的胃癌患者帶來新的希望。

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江蘇省自然科學(xué)基金項目(BK201508)

作者單位： 221006 江蘇 徐州，徐州醫(yī)科大學(xué)附屬醫(yī)院 胃腸外科

朱孝成，Email: zxchl@yahoo.com

10.3969/j.issn.1674-4136.2017.02.017

1674-4136(2017)02-0125-04

2016-12-25][本文編輯：李慶]