*第一作者：賀飛飛(1987—)，男，在讀碩士研究生。研究方向：中醫(yī)藥防治腫瘤疾病。E-mail：sxlllshefei@126.com。

髓系來源抑制細(xì)胞調(diào)控腫瘤機(jī)制的研究進(jìn)展

*第一作者：賀飛飛(1987—)，男，在讀碩士研究生。研究方向：中醫(yī)藥防治腫瘤疾病。E-mail：sxlllshefei@126.com。

★賀飛飛1*王剛2應(yīng)栩華2**(1.浙江中醫(yī)藥大學(xué)第二臨床學(xué)院杭州 310053；2.浙江省立同德醫(yī)院中西醫(yī)結(jié)合腫瘤研究所杭州 310012)

摘要：髓系來源抑制細(xì)胞(Myeloid-derived suppressor cells，MDSCs)是一群未成熟的髓系來源細(xì)胞，參與了腫瘤的增殖、侵潤、腫瘤血管生成、免疫抑制等病理過程，促進(jìn)腫瘤的發(fā)生和生長；反過來，腫瘤以及腫瘤微環(huán)境也可促使MDSCs進(jìn)一步增殖。本文就MDSCs的產(chǎn)生以及和腫瘤之間的相互作用以及部分作用機(jī)制做一綜述。

關(guān)鍵詞：髓系來源抑制細(xì)胞，腫瘤，腫瘤微環(huán)境；綜述

腫瘤的發(fā)生是一個極復(fù)雜的、多步驟的、長期漸變的過程，這一過程是以復(fù)雜的腫瘤微環(huán)境(Tumor Microenvironment，TME)為背景，在這一微環(huán)境中，腫瘤發(fā)生、發(fā)展和轉(zhuǎn)移等事件依次發(fā)生[1]。腫瘤微環(huán)境中有多種免疫細(xì)胞，淋巴細(xì)胞、自然殺傷細(xì)胞(NK細(xì)胞)、單核/巨噬細(xì)胞、間質(zhì)細(xì)胞和分化不完全的骨髓細(xì)胞等，同時其間充盈著多種細(xì)胞因子，諸如IL-1、IL-8、TNF-α等細(xì)胞/趨化因子[2]。越來越多的證據(jù)顯示，腫瘤細(xì)胞在發(fā)生、增殖和轉(zhuǎn)移,逃脫免疫監(jiān)視和免疫抑制的過程中，一組被稱為髓系來源抑制性細(xì)胞(Myeloid-derived suppressor cells，MDSCs)能夠顯著抑制腫瘤特異性免疫[3]。MDSCs是一群異質(zhì)性細(xì)胞群，這些細(xì)胞一般來源于分化不完全的骨髓細(xì)胞，能夠聚集在腫瘤微環(huán)境中，分泌多種細(xì)胞因子，發(fā)揮腫瘤免疫抑制作用。本文將就MDSCs的特征、形成以及MDSCs在腫瘤免疫抑制中的相關(guān)機(jī)制作一綜述。

1MDSCs的特征及發(fā)生過程

1.1MDSCs的認(rèn)識歷程20世紀(jì)初，人們認(rèn)識腫瘤的特征之一就是骨髓外血細(xì)胞發(fā)生(Extramedullary Haematopoiesis)和中性粒細(xì)胞數(shù)量增加[4]，后來證實(shí)這一過程有利于腫瘤免疫逃逸和腫瘤內(nèi)血管形成。這一特征導(dǎo)致腫瘤細(xì)胞和骨髓祖細(xì)胞的相互影響[5]。由于這一特征細(xì)胞表現(xiàn)出抑制淋巴細(xì)胞和細(xì)胞毒性T細(xì)胞活性，被稱為自然抑制細(xì)胞(Natural suppressor，NS)[6]。由于這些細(xì)胞缺乏像成熟T細(xì)胞、B細(xì)胞類似的表面標(biāo)志，因此被稱為Null細(xì)胞[7]。在2007年由Dmitry I. Gabrilovich等建議，引入髓系來源抑制性細(xì)胞(MDSCs)的概念，來反映這一細(xì)胞群體的特征[8]。

1.2MDSCs的來源及特征

1.2.1小鼠MDSCs由于缺乏相應(yīng)的表型標(biāo)志物，最初人們對小鼠MDSCs細(xì)胞的表型特征存在有爭議[6]。隨后，逐漸確認(rèn)了其表面標(biāo)記物，包括CD34、谷胱甘肽還原酶或CD11b[9]。在淋巴細(xì)胞抗原Ly-6C和Ly-6G表達(dá)的基礎(chǔ)上發(fā)現(xiàn)了將小鼠MDSCs細(xì)胞群區(qū)分開的細(xì)胞標(biāo)記物，將MDSCs分為單核細(xì)胞-MDSCs(Mo-MDSCs)[10]和粒細(xì)胞-MDSCs(G-MDSCs)。同時證實(shí)，荷瘤小鼠的MDSCs主要亞群是G-MDSCs[10]。進(jìn)一步的研究發(fā)現(xiàn)，G-MDSCs的亞群主要是GR1bright，Mo-MDSCs的亞群是GR1int[11]。

腫瘤相關(guān)巨噬細(xì)胞(tumor associated macrophages TAM)是一群組織結(jié)構(gòu)易與MDSCs混淆的細(xì)胞[12]。其功能相似性主要表現(xiàn)在MDSCs和TAM均表達(dá)IL-4受體α(IL4Rα)、巨噬細(xì)胞CSF受體(M-CSFR，也稱為CD115)[13]。根據(jù)iNOS的表達(dá)將TAM和Mo-MDSCs的分化和成熟階段區(qū)別開來，iNOS+的MDSCs表達(dá)粒細(xì)胞標(biāo)記物(包括趨化因子受體2(CXCR2)和Ly-6G)[14]。多項(xiàng)長期的研究發(fā)現(xiàn)，嚙齒動物與人類的MDSCs亞群性質(zhì)基本一致，它們具有相似表型[15]。

1.2.2人類MDSCs上世紀(jì)90年代中期，用粒細(xì)胞集落刺激因子(G-CSF)或人粒細(xì)胞-巨噬細(xì)胞集落刺激因子(GM-CSF)誘導(dǎo)干細(xì)胞的活化，采用自體外周血干細(xì)胞移植的方法治療乳腺癌或淋巴瘤病人，同時發(fā)現(xiàn)了一種來自外周血干細(xì)胞(Peripheral blood stem cells，PBSC)，對T細(xì)胞有抑制作用的髓系細(xì)胞，被定義為抑制性CD14+單核細(xì)胞[16]。90年代后期，隨著被發(fā)現(xiàn)的MDSCs表型增多，進(jìn)一步研究發(fā)現(xiàn)，癌癥患者中，共同表達(dá)的MDSCs標(biāo)志物是CD33和/或CD11b，以及LIN-和/或HLA-DR-。目前，在CD14low或CD15+表達(dá)的基礎(chǔ)上，將人MDSCs劃分為LIN HLA-DR 和CD11b+或CD33+兩個亞群。對MDSCs亞群的識別，驗(yàn)證了MDSCs的可塑性及其潛在的分化能力，其不僅可以分化為粒細(xì)胞，單核細(xì)胞和DC，而且可以分化為破骨細(xì)胞和內(nèi)皮細(xì)胞。MDSCs在外周血中占有很大的比例(在數(shù)量和功能上)，可以促進(jìn)腫瘤浸潤、生長和進(jìn)展[17]?；谛∈蠛腿祟怣DSCs的可塑性，MDSCs根據(jù)不同的環(huán)境信號(包括細(xì)胞因子、生長因子和葡萄糖水平等)表現(xiàn)不同的功能。

2MDSCs與腫瘤相互作用

2.1骨髓細(xì)胞和腫瘤之間的交叉調(diào)節(jié)機(jī)制荷瘤機(jī)體的造血功能異常，最初被認(rèn)為是中性粒細(xì)胞增多和大量不成熟的細(xì)胞導(dǎo)致的[18]；后來的研究發(fā)現(xiàn)，此現(xiàn)象與腫瘤分泌的細(xì)胞因子和趨化因子誘導(dǎo)的骨髓細(xì)胞增殖、積累以及腫瘤浸潤有關(guān)[19]。機(jī)體腫瘤微環(huán)境和腫瘤分泌的細(xì)胞因子刺激MDSCs，后者做出相應(yīng)反應(yīng)。外周血中的細(xì)胞因子和趨化因子在不同的荷瘤機(jī)體之間，都存在有顯著的差別，這些因子會誘導(dǎo)MDSCs發(fā)生腫瘤依賴性增殖，以及在腫瘤位點(diǎn)積累和浸潤；綜合這些因素，使得很難確定腫瘤微環(huán)境中MDSCs活動的關(guān)鍵因素。Gibb等[20]研究發(fā)現(xiàn)，腫瘤分泌的生長因子不僅可以誘導(dǎo)骨髓造血和趨化因子活化，而且可以動員和圍繞MDSCs，同時它們也可能參與限制MDSCs的成熟和分化，最終促進(jìn)腫瘤細(xì)胞的累積。例如，腫瘤壞死因子(TNF)，通過調(diào)節(jié)受體TOR的晚期糖化終產(chǎn)物(RAGE，也稱為MOK)及其配體(S100A8和S100A9)[21]，阻止MDSCs的成熟[22]。另外，炎性介質(zhì)如IL-1β、IL-6、白三烯D4(LTD4)和前列腺素E2(PGE2)，也參與調(diào)節(jié)MDSCs的積累和活化。小鼠模型[10]實(shí)驗(yàn)研究證實(shí)，在調(diào)節(jié)MDSCs的增殖、累積和轉(zhuǎn)移過程中存在異質(zhì)性。

2.2MDSCs與腫瘤的增殖調(diào)控在腫瘤條件培養(yǎng)基(Tumor conditioned medium，TCM)中分別加入離出的骨髓細(xì)胞或祖細(xì)胞亞群[23]，發(fā)現(xiàn)其中存在一種介質(zhì)使MDSCs得以存活、增殖、分化和發(fā)揮功能。進(jìn)一步的研究證實(shí)，腫瘤分泌VEGFA(血管內(nèi)皮生長因子Vascular endothelial growth factor)[24]、干細(xì)胞因子(SCF)[25]等因子，都可以刺激MDSCs增殖。體外移植瘤的研究發(fā)現(xiàn)，剔除腫瘤細(xì)胞中的GM-CSF后，隨著腫瘤的生長，MDSCs數(shù)量和亞群分布發(fā)生了改變[26]。與這種研究方法相似，使用GM-CSF和GM-CSF受體[27]、VEGFA[28]等的分子抑制物，腫瘤微環(huán)境中MDSCs的積累和募集受到抑制，并且腫瘤進(jìn)展也會相應(yīng)受到抑制。Mauro等[29]利用乳腺癌小鼠模型(BALB-NEUT小鼠)實(shí)驗(yàn)發(fā)現(xiàn)，腫瘤進(jìn)展和具有免疫抑制活性的不成熟GR1+CD11b+CD131+細(xì)胞數(shù)量之間有直接的關(guān)系。

體外研究證實(shí)，TCM可促進(jìn)KIT+MDSCs前體的增殖[30]，并且主要產(chǎn)生GR1+CD11b+細(xì)胞群。進(jìn)一步觀察發(fā)現(xiàn)，TCM中加入中和GM-CSF的抗體后，終止了從KIT+MDSCs前體到MDSCs的增殖；但是培養(yǎng)基中加入其他細(xì)胞因子的中和抗體后，都沒有觀察到這種結(jié)果，這表明GM-CSF是產(chǎn)生免疫抑制性MDSCs所必需的細(xì)胞因子[30]。

此外，炎癥蛋白S100A8和S100A9對MDSCs增殖也有促進(jìn)作用，而且能夠阻止骨髓前體細(xì)胞的分化。S100A8和S100A9在腫瘤微環(huán)境中高表達(dá)，可能對MDSCs的募集也有促進(jìn)作用[31]。另外，基質(zhì)金屬蛋白酶9(MMP9)可以促進(jìn)MDSCs增殖，甚至促進(jìn)腫瘤組織血管生成，刺激VEGFA的產(chǎn)生等[32]。

2.3MDSCs調(diào)控腫瘤的侵潤腫瘤細(xì)胞和MDSCs分泌的部分酶能夠促進(jìn)腫瘤侵襲，有報(bào)道稱微環(huán)境下蛋白酶濃度和腫瘤的惡性程度之間之間存在正相關(guān)關(guān)系[33]。MicroRNA-494 (miR-494)[23]和HIF1α[34]既能夠調(diào)控MDSCs抑制免疫的功能，也可以促進(jìn)MDSCs侵潤到腫瘤組織；miR-494通過上調(diào)MMP(基質(zhì)金屬蛋白酶Matrix metalloproteinases)增強(qiáng)腫瘤侵襲能力[23]。MDSCs在乳腺癌發(fā)病過程中專門驅(qū)動骨轉(zhuǎn)移[35]。研究發(fā)現(xiàn)缺乏II型轉(zhuǎn)化生長因子-β(TGFβ)受體的乳腺癌模型[36]，腫瘤轉(zhuǎn)移的發(fā)生率和MDSCs的腫瘤浸潤明顯提高。

2.4MDSCs調(diào)節(jié)腫瘤血管發(fā)生和血管生成近來有報(bào)道稱，微環(huán)境侵潤和外周循環(huán)的MDSCs對腫瘤血管生成和血管發(fā)生也有促進(jìn)作用。腫瘤生長導(dǎo)致抑制和刺激腫瘤血管生成的分子之間的不平衡，從而導(dǎo)致內(nèi)皮細(xì)胞增殖和募集。造血亢進(jìn)和內(nèi)皮祖細(xì)胞(Endothelial progenitor cells EPC)的增殖導(dǎo)致MDSCs在外周血中的循環(huán)量增多，進(jìn)而和腫瘤分泌的趨化因子募集到新生的腫瘤病灶(包括原發(fā)性和繼發(fā)性)，促進(jìn)新生血管的生成。而且血管密度和腫瘤分化期數(shù)呈正相關(guān)關(guān)系[37]。

骨髓來源的EPC募集、遷移、增殖和分化也有助于腫瘤血管的形成[38]。生長因子、內(nèi)皮祖細(xì)胞也參與腫瘤血管生成[39]。進(jìn)一步研究發(fā)現(xiàn)，抑制EPC動員可延緩或抑制腫瘤的生長[40]。Lewis肺癌小鼠和B16黑色素瘤小鼠的研究發(fā)現(xiàn)，盡管兩種小鼠腫瘤模型的微血管水平相似，但是Lewis肺癌小鼠體內(nèi)發(fā)現(xiàn)了高水平的EPC，而在B16黑色素瘤小鼠體內(nèi)并未檢測到EPC[41]。G-CSF和VEGFA動員EPC到外周血循環(huán)，促進(jìn)血管生成[42]。脾MDSCs可直接分化成EPC促進(jìn)腫瘤血管發(fā)生[43]；EPC可以動員腫瘤分泌VEGFA、G-CSF或GM-CSF，有助于腫瘤血管形成[44]。相對于荷瘤小鼠，注射G-CSF的非荷瘤小鼠不增加循環(huán)EPC的含量，這表明EPC的生成需要另外的腫瘤相關(guān)細(xì)胞因子，如VEGFA可以從骨髓動員EPC[45]。

2.5MDSCs調(diào)控宿主防御腫瘤微環(huán)境一旦形成，對宿主免疫功能有抑制作用。腫瘤微環(huán)境可以通過多種機(jī)制，包括腫瘤分泌的因子及其引起的組織穩(wěn)態(tài)的變化，下調(diào)抗腫瘤免疫反應(yīng)。在腫瘤進(jìn)展和免疫治療之間，腫瘤細(xì)胞群可能選擇性增強(qiáng)對免疫監(jiān)視和免疫治療的抑制力。另外，腫瘤細(xì)胞變異體的出現(xiàn)，可以干擾免疫細(xì)胞發(fā)育、分化、遷移和細(xì)胞毒性的多個階段[46]。因此，抗腫瘤免疫很多方面都受到腫瘤微環(huán)境的影響[47]。

由于腫瘤患者體內(nèi)普遍存在MDSCs，并且MDSCs與疾病進(jìn)展和不良預(yù)后有關(guān)[48]，近年,MDSCs逐漸成為新的腫瘤免疫研究焦點(diǎn)。免疫抑制在癌癥早期就已經(jīng)出現(xiàn)，并且隨著腫瘤的長大而逐漸增強(qiáng)；同時，MDSCs數(shù)量的增加可以抑制NK細(xì)胞功能[49]。

2.6MDSCs調(diào)節(jié)免疫抑制的分子機(jī)制MDSCs通過多種機(jī)制抑制機(jī)體的免疫功能，包括產(chǎn)生多種細(xì)胞因子抑制NK細(xì)胞、巨噬細(xì)胞、T細(xì)胞等的活性。MDSCs表面的TGF-β可以介導(dǎo)MDSCs下調(diào)NK細(xì)胞表面受體NKG2D(一種Ⅱ型凝集素樣蛋白)，抑制NK細(xì)胞的殺傷力，且這種關(guān)系有賴于細(xì)胞和細(xì)胞之間的直接接觸[50]。MDSCs通過其細(xì)胞膜表達(dá)的ADAM17(一種解聚素和金屬蛋白酶結(jié)構(gòu)域17)裂解L-選擇素的胞外結(jié)構(gòu)域[51]，導(dǎo)致初始T細(xì)胞歸巢到淋巴結(jié)的能力下降，T細(xì)胞免疫功能受到抑制，甚至T細(xì)胞的效應(yīng)消失。MDSCs表達(dá)高水平的精氨酸酶-1，導(dǎo)致L-精氨酸分解代謝增強(qiáng)，進(jìn)而抑制T細(xì)胞增殖。另外在腫瘤微環(huán)境下產(chǎn)生的細(xì)胞因子如TGF-β、IL-3以及GM-CSF等能夠誘導(dǎo)MDSCs產(chǎn)生活性氧簇(ROS)[52]，Nagara等研究發(fā)現(xiàn)MDSCs和T細(xì)胞直接接觸，使T細(xì)胞的特異性抗原肽結(jié)構(gòu)改變，T細(xì)胞對抗原特異性的刺激產(chǎn)生無應(yīng)答反應(yīng)[53]。

2.7MDSCs在腫瘤治療中的作用研究發(fā)現(xiàn)，有很多酶、生長因子和細(xì)胞因子參與調(diào)控MDSCs。這些分子抑制劑包括多種靶向酪氨酸激酶藥物，如cGMP特異性3',5'-環(huán)狀磷酸二酯酶(PDE5A)[54]和COX2等。近幾年在MDSCs病理生理方面的研究有了新的進(jìn)展[55]，例如VEGFR2(也稱為FLK1和KDR)酪氨酸激酶抑制劑(TKIs)，靶向作用于血管生成，而且對抑制腫瘤生長有一定作用。在臨床上，應(yīng)用舒尼替尼可顯著降低轉(zhuǎn)移性腎細(xì)胞癌患者外周血中MDSCs濃度[56]。臨床前期的腫瘤模型中觀察到，骨髓來源的髓系細(xì)胞能產(chǎn)生VEGFA，并且能夠逃脫VEGFA抑制劑的抑制作用[57]。

3結(jié)論

MDSCs一群是未成熟的異質(zhì)性造血細(xì)胞，具有誘導(dǎo)免疫耐受、促進(jìn)腫瘤進(jìn)展和轉(zhuǎn)移的作用。近年來，在腫瘤學(xué)研究領(lǐng)域中MDSCs及其生物功能得到極大的關(guān)注。MDSCs在腫瘤病理過程中的作用遠(yuǎn)遠(yuǎn)超出了對免疫抑制的作用。從目前了解的關(guān)于MDSCs促進(jìn)腫瘤增殖、促進(jìn)腫瘤微環(huán)境中血管發(fā)生及生成、甚至對免疫抑制等作用來看，減少M(fèi)DSCs數(shù)量，逆轉(zhuǎn)其功能，將十分有助于腫瘤的治療。因此，目前很多研究集中在如何減少、甚至消除MDSCs數(shù)量和功能。但是關(guān)于造血祖細(xì)胞的異常分化成MDSCs的機(jī)制、MDSCs遷移至外周淋巴器官的分子機(jī)制等仍然有待進(jìn)一步研究闡明。

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The Research Progress of Mechanism of Regulating Tumor with Myeloid-derived Suppressor Cells

HE Fei-fei1,WANG Gang2,YING Xu-hua2

1.ZhejiangChineseMedicalUniversity,Hangzhou310053,China;

2.CancerInstituteofIntegrativeMedicine,TongdeHospitalofZhejiangProvince,Hangzhou310012,China.

Abstract:A group of immature myeloid-derived cells called Myeloid-derived suppressor cells (MDSCs) which involved in tumor proliferation, invasion and pathological processes, and promote tumorigenesis and growth; and the tumor microenvironment may also induce MDSCs further proliferation. This article will do a review about the MDSCs on the generation and interaction between tumor and part of the mechanism.

Key words:Myeloid-derived Suppressor Cells (MDSCs); Tumour; Tumor Microenvironment

收稿日期：(2014-12-20)編輯：王河寶

中圖分類號：R73

文獻(xiàn)標(biāo)識碼：B

通信作者：**應(yīng)栩華(1961—)，女，主任中醫(yī)師。研究方向：中醫(yī)藥防治腫瘤疾病。E-mail：yyingxh@163.com。