髓系來(lái)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。

髓系來(lái)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(lái)源抑制細(xì)胞(Myeloid-derived suppressor cells，MDSCs)是一群未成熟的髓系來(lái)源細(xì)胞，參與了腫瘤的增殖、侵潤(rùn)、腫瘤血管生成、免疫抑制等病理過(guò)程，促進(jìn)腫瘤的發(fā)生和生長(zhǎng)；反過(guò)來(lái)，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(lái)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(gè)極復(fù)雜的、多步驟的、長(zhǎng)期漸變的過(guò)程，這一過(guò)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(shí)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(lái)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(guò)程中，一組被稱為髓系來(lái)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(lái)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(guò)程

1.1MDSCs的認(rèn)識(shí)歷程20世紀(jì)初，人們認(rèn)識(shí)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(lái)證實(shí)這一過(guò)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(lái)源抑制性細(xì)胞(MDSCs)的概念，來(lái)反映這一細(xì)胞群體的特征[8]。

1.2MDSCs的來(lái)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(duì)小鼠MDSCs細(xì)胞的表型特征存在有爭(zhēng)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(kāi)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(shí)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(kāi)來(lái)，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(zhǎng)期的研究發(fā)現(xiàn)，嚙齒動(dòng)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(shí)發(fā)現(xiàn)了一種來(lái)自外周血干細(xì)胞(Peripheral blood stem cells，PBSC)，對(duì)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L(zhǎng)IN HLA-DR 和CD11b+或CD33+兩個(gè)亞群。對(duì)MDSCs亞群的識(shí)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(rùn)、生長(zhǎng)和進(jìn)展[17]。基于小鼠和人類MDSCs的可塑性，MDSCs根據(jù)不同的環(huán)境信號(hào)(包括細(xì)胞因子、生長(zhǎng)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(lái)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(rùn)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(huì)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(rùn)；綜合這些因素，使得很難確定腫瘤微環(huán)境中MDSCs活動(dòng)的關(guān)鍵因素。Gibb等[20]研究發(fā)現(xiàn)，腫瘤分泌的生長(zhǎng)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(dòng)員和圍繞MDSCs，同時(shí)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(guò)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(guò)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(zhǎng)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(zhǎng)，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(huì)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(méi)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(duì)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(duì)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(rùn)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(rùn)到腫瘤組織；miR-494通過(guò)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(guò)程中專門(mén)驅(qū)動(dòng)骨轉(zhuǎn)移[35]。研究發(fā)現(xiàn)缺乏II型轉(zhuǎn)化生長(zhǎng)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(rùn)明顯提高。

2.4MDSCs調(diào)節(jié)腫瘤血管發(fā)生和血管生成近來(lái)有報(bào)道稱，微環(huán)境侵潤(rùn)和外周循環(huán)的MDSCs對(duì)腫瘤血管生成和血管發(fā)生也有促進(jìn)作用。腫瘤生長(zhǎng)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(lái)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(zhǎng)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(dòng)員可延緩或抑制腫瘤的生長(zhǎng)[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(cè)到EPC[41]。G-CSF和VEGFA動(dòng)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(dòng)員腫瘤分泌VEGFA、G-CSF或GM-CSF，有助于腫瘤血管形成[44]。相對(duì)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(dòng)員EPC[45]。

2.5MDSCs調(diào)控宿主防御腫瘤微環(huán)境一旦形成，對(duì)宿主免疫功能有抑制作用。腫瘤微環(huán)境可以通過(guò)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(duì)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(gè)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(zhǎng)大而逐漸增強(qiáng)；同時(shí)，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(guò)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(guò)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(duì)抗原特異性的刺激產(chǎn)生無(wú)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(zhǎng)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(duì)抑制腫瘤生長(zhǎng)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(lái)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(lái)，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(guò)程中的作用遠(yuǎn)遠(yuǎn)超出了對(duì)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(duì)免疫抑制等作用來(lái)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。

參考文獻(xiàn)

[1]Taddei ML, Giannoni E, Comito G, et al. Microenvironment and tumor cell plasticity: an easy way out. [J].Cancer Lett，.2013. 341(1): 80-96.

[2]Van den Heuvel MM, Burgers SA, van Zandwijk N. Immunotherapy in non-small-cell lung carcinoma: from inflammation to vaccination[J].Clin Lung Cancer, 2009,10(2): 99-105.

[3]Talmadge JEI, Gabrilovich DI.History of myeloid-derived suppressor cells[J].Nat Rev Cancer, 2013,13(10): 739-752.

[4]Hinshaw DB, Hoxie HJ. Leukemoid reactions in carcinomas[J].Calif Med, 1949,71(4): 300.

[5]Robinson W.A. Granulocytosis in neoplasia. Granulocytosis in neoplasia[J].Ann N Y Acad Sci, 1974,230: 212-218.

[6]Bennett JA, Rao VS, Mitchell MS. Systemic bacillus Calmette-Guerin (BCG) activates natural suppressor cells[J].Proc Natl Acad Sci U S A.1978, 75(10):5 142-5 144.

[7]Slavin S, Strober S.Induction of allograft tolerance after total lymphoid irradiation (TLI): development of suppressor cells of the mixed leukocyte reaction (MLR) [J].J Immunol, 1979, 123(2): 942-946.

[8]Gabrilovich DI, Bronte V, Chen SH, et al. The terminology issue for myeloid-derived suppressor cells[J].Cancer Res,2007, 67(1): 425- 426.

[9]Sy MS, Miller SD, Claman HN. Immune suppression with supraoptimal doses of antigen in contact sensitivity. I. Demonstration of suppressor cells and their sensitivity to cyclophosphamide[J].J Immunol, 1977, 119(1): 240-244.

[10]Youn JI, Nagaraj S, Collazo M, et al. Subsets of myeloid-derived suppressor cells in tumor-bearing mice[J].J Immunol, 2008,181(8): 5 791-5 802.

[11]Waight JD, Hu Q, Miller A, et al. Tumor-derived G-CSF facilitates neoplastic growth through a granulocytic myeloid-derived suppressor cell-dependent mechanism[J].PLoS One, 2011, 6(11): e27 690.

[12]Movahedi K, Laoui D, Gysemans C, et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes[J].Cancer Res, 2010, 70(14): 5 728-5 739.

[13]Gabrilovich DI,Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system[J].Nat Rev Immunol, 2009,9(3): 162-174.

[14]Virtuoso LP, Harden JL, Sotomayor P, et al.Characterization of iNOS(+) Neutrophil-like ring cell in tumor-bearing mice[J].J Transl Med, 2012, 10: 152.

[15]Brandau S, Moses K, Lang S. The kinship of neutrophils and granulocytic myeloid-derived suppressor cells in cancer: cousins, siblings or twins [J].Semin Cancer Biol, 2013, 23(3): 171-182.

[16]Laoui D, Van Overmeire E, Movahedi K, et al. Mononuclear phagocyte heterogeneity in cancer: different subsets and activation states reaching out at the tumor site[J].Immunobiology, 2011, 216(11): 1 192-1 202.

[17]Mantovani A, Sica A, Macrophages. Innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol, 2010,22(2): 231-237.

[18]Glasser LRI, Fiederlein RL, Fiederlein. Functional differentiation of normal human neutrophils[J].Blood, 1987,69(3): 937-944.

[19]DuPre SA, Hunter KW Jr.Murine mammary carcinoma 4T1 induces a leukemoid reaction with splenomegaly: association with tumor-derived growth factors[J].Exp Mol Pathol, 2007,82(1): 12-24.

[20]Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development[J].J Clin Invest, 2007, 117(5):1 155-1 166.

[21]Cheng P, Corzo CA, Luetteke N, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein[J].J Exp Med, 2008, 205(10):2 235-2 249.

[22]Sade-Feldman M, Kanterman J, Ish-Shalom E, et al.Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation[J].Immunity, 2013, 38(3): 541-554.

[23]Liu Y, Lai L, Chen Q, et al. MicroRNA-494 is required for the accumulation and functions of tumor-expanded myeloid-derived suppressor cells via targeting of PTEN[J].J Immunol, 2012, 188(11): 5 500-5 510.

[24]Melani C, Chiodoni C, Forni G, et al.Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity[J].Blood, 2003. 102(6):2 138-2 145.

[25]Pan PY, Wang GX, Yin B, et al.Reversion of immune tolerance in advanced malignancy: modulation of myeloid-derived suppressor cell development by blockade of stem-cell factor function[J].Blood, 2008, 111(1): 219-228.

[26]Dolcetti L, Peranzoni E, Ugel S, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF[J].Eur J Immunol, 2010,40(1): 22-35.

[27]Ko JS, Rayman P, Ireland J, et al. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res, 2010, 70(9):3 526-3 536.

[28]Fricke I, Mirza N, Dupont J, et al. Vascular endothelial growth factor-trap overcomes defects in dendritic cell differentiation but does not improve antigen-specific immune responses[J].Clin Cancer Res, 2007. 13(16): 4 840-4 848.

[29]Melani C, Chiodoni C, Forni G, et al.Myeloid cell expansion elicited by the progression of spontaneous mammary carcinomas in c-erbB-2 transgenic BALB/c mice suppresses immune reactivity[J].Blood, 2003,102(6): 2 138-2 145.

[30]Bayne LJ, Beatty GL, Jhala N, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer[J].Cancer Cell, 2012, 21(6):822-835.

[31]Sinha P, Okoro C, Foell D, et al. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells[J].J Immunol, 2008, 181(7): 4 666-4 675.

[32]Yang L, DeBusk LM, Fukuda K, et al.Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis[J].Cancer Cell, 2004, 6(4): 409-421.

[33]Stenvold H, Donnem T, Andersen S, et al. Overexpression of matrix metalloproteinase-7 and -9 in NSCLC tumor and stromal cells: correlation with a favorable clinical outcome[J].Lung Cancer, 2012, 75(2):235-241.

[34]Corzo CA, Condamine T, Lu L, et al. HIF-1alpha regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment[J].J Exp Med, 2010,207(11): 2 439-2 453.

[35]Sawant A, Deshane J, Jules J, et al. Myeloid-derived suppressor cells function as novel osteoclast progenitors enhancing bone loss in breast cancer[J].Cancer Res, 2013, 73(2):672-682.

[36]Yang L, Huang J, Ren X, et al. Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1+CD11b+ myeloid cells that promote metastasis[J].Cancer Cell, 2008,13(1): 23-35.

[37]Nishie A, Ono M, Shono T, et al. Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas[J].Clin Cancer Res, 1999. 5(5): 1 107-1 113.

[38]Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis[J].Science, 1997. 275(5302): 964-967.

[39]Nolan DJ, Ciarrocchi A, Mellick AS, et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization[J].Genes Dev, 2007,21(12): 1 546-1 558.

[40]Davidoff AM, Ng CY, Brown P, et al. Bone marrow-derived cells contribute to tumor neovasculature and, when modified to express an angiogenesis inhibitor, can restrict tumor growth in mice[J].Clin Cancer Res, 2001, 7(9): 2 870-2 879.

[41]Mulligan JK1, Rosenzweig SA, Young MR. Tumor secretion of VEGF induces endothelial cells to suppress T cell functions through the production of PGE2[J].J Immunother, 2010,33(2): 126-135.

[42]Madlambayan GJ, Butler JM, Hosaka K, et al. Bone marrow stem and progenitor cell contribution to neovasculogenesis is dependent on model system with SDF-1 as a permissive trigger[J].Blood, 2009,114(19): 4 310-4 319.

[43]Dome B, Timar J, Dobos J, et al. Identification and clinical significance of circulating endothelial progenitor cells in human non-small cell lung cancer[J].Cancer Res, 2006,66(14): 7 341-7 347.

[44]Lyden D, Hattori K, Dias S, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth[J].Nat Med, 2001,7(11): 1 194-1 201.

[45]Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells[J].EMBO J, 1999. 18(14): 3 964-3 972.

[46]Talmadge JE,Fidler IJ. AACR centennial series: the biology of cancer metastasis: historical perspective[J].Cancer Res, 2010, 70(14): 5 649-5 669.

[47]Whiteside TL. The tumor microenvironment and its role in promoting tumor growth[J].Oncogene, 2008, 27(45): 5 904-5 912.

[48]Poschke I ,Kiessling R.On the armament and appearances of human myeloid-derived suppressor cells[J].Clin Immunol, 2012,144(3): 250-268.

[49]Zhao F, Obermann S, von Wasielewski R, et al. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma[J].Immunology, 2009, 128(1): 141-149.

[50]Li H, Han Y, Guo Q, et al. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1[J].J Immunol, 2009, 182(1): 240-249.

[51]Li X, Pérez L, Pan Z, et al. The transmembrane domain of TACE regulates protein ectodomain shedding[J].Cell Res, 2007. 17(12): 985-998.

[52]Paduch R, Kandefer-Szerszeń M, Piersiak T. The importance of release of proinflammatory cytokines, ROS, and NO in different stages of colon carcinoma growth and metastasis after treatment with cytotoxic drugs[J].Oncol Res, 2010, 18(9): 419-436.

[53]Wolf AM, Rumpold H, Tilg H, et al.The effect of zoledronic acid on the function and differentiation of myeloid cells[J].Haematologica, 2006, 91(9): 1 165-1 171.

[54]Serafini P, Meckel K, Kelso M, et al. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function[J].J Exp Med, 2006,203(12): 2 691-2 702.

[55]Montero AJ, Diaz-Montero CM, Kyriakopoulos CE, et al. Myeloid-derived suppressor cells in cancer patients: a clinical perspective[J].J Immunother, 2012, 35(2): 107-115.

[56]Van Cruijsen H, Van Der Veldt AA, Vroling L, et al. Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c+ dendritic cell frequency predicts progression-free survival[J].Clin Cancer Res, 2008, 14(18): 5 884-5 892.

[57]Finke J, Ko J, Rini B, et al.MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy[J].Int Immunopharmacol, 2011, 11(7): 856-861.

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(hào)：R73

文獻(xiàn)標(biāo)識(shí)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。