促進(jìn)轉(zhuǎn)移的腫瘤相關(guān)免疫細(xì)胞與靶向治療策略

羅　琴(綜述)　邵衛(wèi)清　楊璐宇　余光陽　欽倫秀,△(審校)

(1復(fù)旦大學(xué)生物醫(yī)學(xué)研究院　上海　200032;2復(fù)旦大學(xué)附屬華山醫(yī)院普外科　上?！?00040;3復(fù)旦大學(xué)腫瘤轉(zhuǎn)移研究所　上?！?00040)

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促進(jìn)轉(zhuǎn)移的腫瘤相關(guān)免疫細(xì)胞與靶向治療策略

羅琴1(綜述)邵衛(wèi)清2,3楊璐宇2,3余光陽1欽倫秀1,2,3△(審校)

(1復(fù)旦大學(xué)生物醫(yī)學(xué)研究院上海200032;2復(fù)旦大學(xué)附屬華山醫(yī)院普外科上海200040;3復(fù)旦大學(xué)腫瘤轉(zhuǎn)移研究所上海200040)

【摘要】腫瘤轉(zhuǎn)移受腫瘤細(xì)胞自身改變的累積和腫瘤微環(huán)境所共同驅(qū)動(dòng)。腫瘤微環(huán)境中的免疫相關(guān)細(xì)胞,尤其是腫瘤相關(guān)巨噬細(xì)胞 (tumor-associated macrophages,TAMs)、骨髓源性抑制細(xì)胞 (myeloid-derived suppressor cells,MDSCs)、調(diào)節(jié)性T細(xì)胞 (regulatory T cells,Treg)等在免疫抑制和促腫瘤轉(zhuǎn)移中舉足輕重。腫瘤轉(zhuǎn)移經(jīng)歷免疫逃逸、預(yù)轉(zhuǎn)移“壁龕”形成、突破血管內(nèi)皮至血循環(huán),最終轉(zhuǎn)移至靶器官形成轉(zhuǎn)移灶，每一個(gè)步驟都離不開腫瘤細(xì)胞與多種免疫細(xì)胞相互作用。本文就免疫相關(guān)細(xì)胞促進(jìn)腫瘤轉(zhuǎn)移的分子機(jī)制作一綜述,并探討靶向腫瘤轉(zhuǎn)移相關(guān)免疫細(xì)胞的研究策略。

【關(guān)鍵詞】腫瘤轉(zhuǎn)移;免疫細(xì)胞;靶向轉(zhuǎn)移相關(guān)免疫細(xì)胞

過去數(shù)十年,我們認(rèn)為在腫瘤發(fā)生發(fā)展過程中免疫系統(tǒng)時(shí)刻監(jiān)視腫瘤并抑制其惡性進(jìn)展。然而,細(xì)胞毒性T細(xì)胞 (cytotoxic T lymphocyte,CTL)和自然殺傷細(xì)胞 (natural killer,NK)作為腫瘤免疫中重要的效應(yīng)細(xì)胞,在巨噬細(xì)胞、中性粒細(xì)胞等免疫細(xì)胞輔助下,雖然確實(shí)發(fā)揮免疫監(jiān)視、免疫抑制和殺傷作用,但事實(shí)上,微環(huán)境中腫瘤細(xì)胞與免疫細(xì)胞之間的相互作用并非如此簡單。在腫瘤發(fā)生過程中,炎性細(xì)胞一方面可產(chǎn)生活性氧 (reactive oxygen species,ROS)和活性氮中間產(chǎn)物 (reactive nitrogen intermediates,RNI),促進(jìn)鄰近上皮細(xì)胞發(fā)生基因突變; 另一方面,則通過分泌的細(xì)胞因子介導(dǎo)上皮細(xì)胞累積ROS和RNI,從基因?qū)用婕氨碛^遺傳學(xué)水平促進(jìn)腫瘤發(fā)生。而在腫瘤發(fā)展過程中,腫瘤浸潤性炎性細(xì)胞,包括調(diào)節(jié)性T細(xì)胞(regulatory T cells,Treg)、巨噬細(xì)胞、樹突狀細(xì)胞、骨髓源性抑制細(xì)胞 (myeloid-derived suppressor cells,MDSCs)等,可分泌多種細(xì)胞因子作用于癌前病變細(xì)胞,活化其NF-κB、STAT3等關(guān)鍵信號通路,促進(jìn)惡性細(xì)胞的生存、增殖、血管新生以及浸潤轉(zhuǎn)移。同時(shí),惡變的實(shí)質(zhì)細(xì)胞也分泌細(xì)胞因子招募各種免疫炎性細(xì)胞,進(jìn)一步形成正向循環(huán),促進(jìn)腫瘤惡性演變[1-2]。

腫瘤惡性轉(zhuǎn)移是導(dǎo)致腫瘤低治愈率、高致死率的直接原因。明確腫瘤轉(zhuǎn)移過程的分子機(jī)制,將為攻克癌癥提供堅(jiān)實(shí)的理論依據(jù)和指導(dǎo)策略。研究表明,腫瘤細(xì)胞轉(zhuǎn)移至靶器官形成轉(zhuǎn)移灶經(jīng)歷了復(fù)雜而漫長的過程。首先,腫瘤細(xì)胞通過特定機(jī)制逃避免疫監(jiān)視,并分泌多種細(xì)胞因子改變靶向轉(zhuǎn)移器官微環(huán)境,為其浸潤轉(zhuǎn)移作準(zhǔn)備。其次,腫瘤細(xì)胞通過多種途徑促進(jìn)血管新生,并增加原發(fā)病灶周圍微血管通透性,促進(jìn)腫瘤細(xì)胞進(jìn)入血液循環(huán)系統(tǒng)。再次,循環(huán)的腫瘤細(xì)胞通過免疫逃逸存活于血液循環(huán),黏附于轉(zhuǎn)移靶器官,并繼續(xù)存活、生長,最終形成轉(zhuǎn)移灶。腫瘤的惡性轉(zhuǎn)移除了與腫瘤細(xì)胞自身內(nèi)在改變有關(guān),依然離不開腫瘤細(xì)胞與微環(huán)境中間質(zhì)細(xì)胞之間的相互作用。尤其是腫瘤浸潤性免疫炎性細(xì)胞及免疫抑制細(xì)胞等,對腫瘤細(xì)胞惡性轉(zhuǎn)移至關(guān)重要。

腫瘤免疫逃逸腫瘤免疫逃逸 (immune escape)指腫瘤細(xì)胞通過特定分子機(jī)制逃避機(jī)體免疫系統(tǒng)識別和攻擊,得以在體內(nèi)存活并增殖的現(xiàn)象。正常情況下,NK細(xì)胞能通過腫瘤缺失的組織相容性分子(major histocompatibility molecules,MHC) I類分子激活相關(guān)配體,繼而激活自身分泌免疫效應(yīng)分子,如IFN-γ。因此,NK細(xì)胞和CTL細(xì)胞數(shù)目往往與腫瘤患者良好預(yù)后相關(guān)。而在腫瘤惡性進(jìn)展過程中,腫瘤細(xì)胞則可以通過分泌免疫抑制分子,如TGF-β、IL-10、ROS等,抑制NK細(xì)胞和CTL細(xì)胞的募集,并改變其細(xì)胞毒性功能及膜表面受體的分布,從而抵御腫瘤的惡性進(jìn)展[3]。不僅如此,腫瘤細(xì)胞也會一方面“改變自我”,另一方面“化敵為友,為我所用”。腫瘤細(xì)胞通過下調(diào)甚至缺失表達(dá)MHC、腫瘤抗原等,而“改變自我”不被免疫細(xì)胞所識別清除,從而逃避免疫監(jiān)視[4]。

腫瘤細(xì)胞實(shí)現(xiàn)“化敵為友”主要通過轉(zhuǎn)變免疫細(xì)胞的抗腫瘤活性,以促進(jìn)自身生長、轉(zhuǎn)移。較為常見的轉(zhuǎn)換包括CD4+T細(xì)胞,從輔助殺傷性T細(xì)胞 (CD8+T細(xì)胞)作用的Th1型向抑制CD8+T細(xì)胞殺傷作用的Th2型轉(zhuǎn)換,巨噬細(xì)胞從主要發(fā)揮吞噬和抗原呈遞作用的M1型向促腫瘤惡性的M2型轉(zhuǎn)變,以及中性粒細(xì)胞從N1型的吞噬作用向N2型的促癌作用轉(zhuǎn)變。據(jù)報(bào)道,腫瘤細(xì)胞可以分泌趨化因子配體22 (CC-chemokine ligand 22,CCL22)、集落刺激因1 (colony-stimulating factor,CSF1)、血管內(nèi)皮生長因子A (vascular endothelial growth factor A,VEGFA)等多種細(xì)胞因子,募集腫瘤相關(guān)巨噬細(xì)胞 (tumour associated macrophages,TAMs)。而募集至腫瘤組織的TAMs通過表達(dá)B7-H4或分泌程序性死亡配體1 (programmed cell death ligand 1,PDL1)[5-6],促進(jìn)CD8+T細(xì)胞凋亡,從而使腫瘤細(xì)胞免受殺傷作用[7]。與巨噬細(xì)胞募集相似,腫瘤細(xì)胞還可分泌趨化因子配體15 (CXC-chemokine ligand 15,CXCL15)和高遷移族蛋白B1 (high mobility group protein B1,HMGB1)等,馴化腫瘤相關(guān)中性粒細(xì)胞 (tumor-associated neutrophils,TANs),從而抑制NK細(xì)胞和CD8+T細(xì)胞的腫瘤清除作用[8]。

免疫抑制細(xì)胞被招募至腫瘤微環(huán)境,形成免疫抑制微環(huán)境,促進(jìn)腫瘤惡性進(jìn)展,已成為研究熱點(diǎn)。免疫抑制細(xì)胞主要包括MDSCs、Treg以及Th17細(xì)胞。研究表明,腫瘤細(xì)胞可通過分泌CXLC1、CXCL5、巨噬細(xì)胞轉(zhuǎn)移抑制因子 (macrophage migration inhibitory factor,MIF)等促進(jìn)MDSCs遷移至腫瘤組織[9]。MDSCs源于骨髓祖細(xì)胞和未成熟的髓細(xì)胞,是樹突狀細(xì)胞、巨噬細(xì)胞和粒細(xì)胞的前體,具有抑制免疫細(xì)胞應(yīng)答的能力。目前尚無直接證據(jù)表明MDSCs能夠促進(jìn)腫瘤轉(zhuǎn)移,但公認(rèn)其免疫抑制功能參與腫瘤免疫逃逸。腫瘤微環(huán)境中募集而來的MDSCs一方面可以通過高表達(dá)一氧化氮合酶2 (nitric oxide synthase 2,NOS2)產(chǎn)生NO,抑制CD8+T細(xì)胞功能,另一方面也可通過精氨酸代謝,氧化T細(xì)胞表面識別受體 (T cell receptor,TCR),使得T細(xì)胞失活[10]。也有文獻(xiàn)報(bào)道MDSCs可分泌IL-6、IL-23和TGFβ等因子募集Th17細(xì)胞,Th17細(xì)胞則通過分泌IL-17分子反作用于MDSCs,促進(jìn)更多MDSCs招募,從而形成正向循環(huán)[9]。不僅如此,腫瘤相關(guān)成纖維細(xì)胞 (cancer associated fibroblasts,CAFs)也可分泌粒細(xì)胞集落刺激因子 (granulocyte colony-stimulating factor,G-CSF)促進(jìn)MDSCs的募集[11]。在免疫逃逸中,Treg也發(fā)揮著非常重要的作用。一方面,腫瘤細(xì)胞可以通過多種細(xì)胞因子(如CCL5、CCL22等)募集到原位腫瘤,協(xié)助腫瘤細(xì)胞獲得惡性表型;另一方面,Treg可促進(jìn)CD8+T細(xì)胞凋亡,進(jìn)而使腫瘤細(xì)胞獲得免疫逃逸,同時(shí)Treg還可以通過誘導(dǎo)NK細(xì)胞凋亡促進(jìn)腫瘤的發(fā)生發(fā)展[12]。此外,也有少量文獻(xiàn)報(bào)道,調(diào)節(jié)性B細(xì)胞 (regulatory B cells,Breg)和漿細(xì)胞樣樹突狀細(xì)胞可以通過調(diào)節(jié)Treg幫助腫瘤細(xì)胞進(jìn)行免疫逃逸,但其相關(guān)機(jī)制尚不明確[13]。

預(yù)轉(zhuǎn)移“壁龕”形成腫瘤細(xì)胞惡性增殖迫于瘤內(nèi)生存壓力及其所處微環(huán)境的調(diào)節(jié),腫瘤細(xì)胞需要找尋新的“殖民地”以滿足自身的生存需求。而在轉(zhuǎn)移至新的“殖民地”即轉(zhuǎn)移靶器官之前,腫瘤細(xì)胞已通過多種途徑改造了靶器官的微環(huán)境,形成有利于其轉(zhuǎn)移和生存的預(yù)轉(zhuǎn)移“壁龕” (pre-metastatic niche)。改造途徑為分泌細(xì)胞因子入血,經(jīng)血液循環(huán)運(yùn)送細(xì)胞至遠(yuǎn)端。研究表明,原位腫瘤細(xì)胞可將一系列細(xì)胞因子分泌入血,包括VEGFA、TGF-β、腫瘤壞死因子 (tumor necrosis factor,TNF)、賴氨酰氧化酶等,到達(dá)靶器官后,誘導(dǎo)趨化性蛋白S100A8、S100A9和血清淀粉樣蛋白A3等表達(dá),從而改變局部微環(huán)境。經(jīng)改造的微環(huán)境可募集不成熟的髓源性細(xì)胞分泌基質(zhì)金屬蛋白酶9 (matrix metalloproteinase 9,MMP9)促進(jìn)腫瘤細(xì)胞轉(zhuǎn)移[14-15]。此外,髓源性細(xì)胞也可通過自身表面的整合素分子與預(yù)轉(zhuǎn)移微環(huán)境中纖連蛋白結(jié)合,從而招募至預(yù)轉(zhuǎn)移微環(huán)境[16]。TAMs及Treg也參與了預(yù)轉(zhuǎn)移微環(huán)境的形成。腫瘤源性纖維蛋白凝塊可促進(jìn)TAMs募集至靶器官,增強(qiáng)腫瘤細(xì)胞惡性表型。同時(shí),腫瘤細(xì)胞分泌的CCL2和CCL22等因子可促進(jìn)Treg遷移至預(yù)轉(zhuǎn)移微環(huán)境,形成免疫抑制微環(huán)境,有助于腫瘤細(xì)胞轉(zhuǎn)移至靶器官后存活并生長[17-18]。不僅細(xì)胞因子可介導(dǎo)腫瘤細(xì)胞改造遠(yuǎn)端微環(huán)境,其代謝產(chǎn)物乳酸也可通過調(diào)節(jié)巨噬細(xì)胞的極化,影響預(yù)轉(zhuǎn)移“壁龕”的形成[19]。近來有研究表明,原位的胰腺癌細(xì)胞可通過外泌體包裹MIF分子作用于Kupffer細(xì)胞,使其產(chǎn)生TGF-β,進(jìn)一步影響遠(yuǎn)端肝組織中的肝星狀細(xì)胞分泌纖連蛋白,形成有利于胰腺癌細(xì)胞肝轉(zhuǎn)移的局部微環(huán)境[20]。可見,外泌體分泌也是腫瘤細(xì)胞調(diào)節(jié)遠(yuǎn)端預(yù)轉(zhuǎn)移“壁龕”的一種重要的方式。

腫瘤細(xì)胞血管浸潤性轉(zhuǎn)移血管新生和侵犯血管是原位腫瘤細(xì)胞播散至遠(yuǎn)端的重要途徑。研究表明,腫瘤組織中高表達(dá)的CSF1結(jié)合TAMs表面受體,激活下游的信號通路,一方面促進(jìn)VEGFA和WNT7B等促血管生成分子的表達(dá)[21-22],另一方面抑制抗血管生成因子產(chǎn)生,最終促進(jìn)血管新生。而新生血管的內(nèi)皮細(xì)胞也可與TAMs相互作用,致使新生血管內(nèi)皮細(xì)胞并非緊密連接,而是以疏松的連接方式相連,從而幫助腫瘤細(xì)胞穿透血管進(jìn)入血循環(huán)[23]。

腫瘤細(xì)胞要突破血管基底膜離不開自身的高浸潤轉(zhuǎn)移能力,而這一能力的獲得與TAMs、TANs等密切相關(guān)。在乳腺癌PyMT模型中發(fā)現(xiàn)TAMs伴隨腫瘤細(xì)胞侵入周圍血管。在侵入過程中,腫瘤細(xì)胞分泌CSF1,通過結(jié)合巨噬細(xì)胞表面受體CSFR1活化奧爾德里奇綜合征蛋白 (Wiskott-Aldrich syndrome protein,WASP)促進(jìn)巨噬細(xì)胞遷移,而遷移過來的巨噬細(xì)胞分泌表皮生長因子 (epidermal growth factor,EGF)反作用于腫瘤細(xì)胞,可進(jìn)一步增強(qiáng)腫瘤細(xì)胞的遷移侵襲能力。除腫瘤細(xì)胞直接分泌因子募集TAMs外,CAFs也可通過分泌CXCL12募集TAMs,參與到腫瘤細(xì)胞與巨噬細(xì)胞的CSF1-EGF 正向循環(huán)[24]。甚至低氧微環(huán)境和CD4+T細(xì)胞來源的IL-4可誘導(dǎo)TAMs分泌組織蛋白酶B和C,重塑細(xì)胞外基質(zhì),以調(diào)節(jié)腫瘤細(xì)胞轉(zhuǎn)移[25-26]。相反,在腫瘤細(xì)胞中敲除類固醇共刺激受體1(steroid receptor co-activator 1,SRC1)則可顯著降低CSF1分泌,進(jìn)而減少所募集的巨噬細(xì)胞數(shù)目[27]。因此,鑒于TAMs在腫瘤侵襲和轉(zhuǎn)移中的重要作用,針對調(diào)控巨噬細(xì)胞亞型轉(zhuǎn)變的關(guān)鍵信號通路設(shè)計(jì)的藥物將有效抑制腫瘤轉(zhuǎn)移。

在具有較高轉(zhuǎn)移能力的人前列腺癌和纖維肉瘤的研究中發(fā)現(xiàn),腫瘤細(xì)胞可以通過募集TANs到原位腫瘤,并通過其分泌的MMP9來促進(jìn)腫瘤轉(zhuǎn)移[28]。肝內(nèi)膽管癌細(xì)胞來源的CXCL15可招募TANs,促進(jìn)其肺轉(zhuǎn)移。盡管有文獻(xiàn)證實(shí)中性粒細(xì)胞可以促進(jìn)腫瘤的轉(zhuǎn)移,但是這一現(xiàn)象仍存在爭議。在乳腺癌自發(fā)轉(zhuǎn)移模型中,去除中性粒細(xì)胞后,肺癌轉(zhuǎn)移增加;從腫瘤小鼠模型腫瘤組織中分離得到的中性粒細(xì)胞在體外能夠通過產(chǎn)生H2O2殺死腫瘤細(xì)胞,過繼回輸這些中性粒細(xì)胞可明顯抑制腫瘤肺轉(zhuǎn)移[29]。

除TAMs和TANs外,MDSCs也參與腫瘤轉(zhuǎn)移。在PyMT腫瘤模型和轉(zhuǎn)基因黑色素瘤小鼠模型中發(fā)現(xiàn),腫瘤細(xì)胞可分泌CXCL5募集MDSCs,后者通過分泌MMPs蛋白促進(jìn)腫瘤轉(zhuǎn)移[30]。而在4T1原位腫瘤模型中發(fā)現(xiàn),腫瘤細(xì)胞還可通過MIF因子募集MDSCs[31]。由于MDSCs是一群未成熟的髓性細(xì)胞,后續(xù)很容易被誘導(dǎo)分化成為巨噬細(xì)胞或樹突狀細(xì)胞,因此尚缺乏有效的技術(shù)手段在體內(nèi)研究MDSCs;并且在不同的臨床腫瘤組織樣本中,尚無統(tǒng)一的MDSCs表面標(biāo)志分子,甚至同一種腫瘤中也存在多群具有不同表面標(biāo)志分子的髓性細(xì)胞,發(fā)揮免疫抑制功能。所以在腫瘤轉(zhuǎn)移過程中,尚未見針對MDSCs進(jìn)行干預(yù)治療的報(bào)道。

腫瘤遠(yuǎn)端轉(zhuǎn)移灶形成腫瘤細(xì)胞脫離原位瘤到達(dá)遠(yuǎn)端形成轉(zhuǎn)移灶,須在血液循環(huán)系統(tǒng)存活并能停留在轉(zhuǎn)移靶器官。這一過程離不開預(yù)轉(zhuǎn)移“壁龕”的提前準(zhǔn)備、免疫逃逸以及TAMs和TANs等免疫細(xì)胞的幫助。血液循環(huán)系統(tǒng)中的腫瘤細(xì)胞可被Treg及TAMs分泌的特定因子激活A(yù)KT、NFκB等信號通路,以提供生存信號[32];也可結(jié)合纖維蛋白和血小板,形成一個(gè)保護(hù)層,逃避NK細(xì)胞的殺傷作用。同時(shí),血小板還可為腫瘤細(xì)胞出血管轉(zhuǎn)移至靶器官提供ATP[33]。另外,TANs可形成中性粒細(xì)胞胞外誘捕網(wǎng) (neutrophil extracellular traps,NETs),促進(jìn)循環(huán)腫瘤細(xì)胞存活和轉(zhuǎn)移。NETs是由中性粒細(xì)胞釋放到胞外,由DNA、抗菌蛋白、組織蛋白酶C及中性粒細(xì)胞彈性蛋白酶等組成的網(wǎng)狀結(jié)構(gòu)。NETs誘捕的腫瘤細(xì)胞可分泌CXCL8,促進(jìn)中性粒細(xì)胞表達(dá)整合素αM,與腫瘤細(xì)胞表達(dá)的細(xì)胞間黏附分子1 (intercellular adhesion molecule 1,ICAM1)結(jié)合,促使腫瘤細(xì)胞黏附在轉(zhuǎn)移靶器官[34-35]。

存活下來的循環(huán)腫瘤細(xì)胞可穿透血管到達(dá)預(yù)轉(zhuǎn)移灶,并與腫瘤微環(huán)境成分進(jìn)一步相互作用得以存活、生長。在PyMT模型中,發(fā)現(xiàn)自發(fā)轉(zhuǎn)移的肺中存在兩種不同類型的巨噬細(xì)胞,一種是與正常肺組織中定居的CD11c+巨噬細(xì)胞一樣,另一種就是募集而來的MAMs。TAMs表達(dá)CD11b、VEGFR1和CCR2,而不表達(dá)GR1、血管生成素1受體 (angiopoietin 1 receptor,TIE2)和CD11c[36]。去除CD11b+巨噬細(xì)胞后,尾靜脈注射乳腺癌細(xì)胞,肺轉(zhuǎn)移明顯減少,可見轉(zhuǎn)移相關(guān)巨噬細(xì)胞的募集對于腫瘤的轉(zhuǎn)移和轉(zhuǎn)移灶生長非常重要。而血液循環(huán)系統(tǒng)中的單核細(xì)胞則是TAMs的一個(gè)重要來源。研究表明,腫瘤細(xì)胞能夠通過分泌CCL2等細(xì)胞因子募集單核細(xì)胞遷移至微轉(zhuǎn)移灶,并誘導(dǎo)成為TAMs,進(jìn)一步分泌產(chǎn)生VEGFA促進(jìn)腫瘤出血管生成和腫瘤細(xì)胞生長[37]。然而,出血管后的腫瘤細(xì)胞如何逃逸轉(zhuǎn)移微環(huán)境中免疫抑制和殺傷作用,相關(guān)機(jī)制尚不明確。

靶向腫瘤轉(zhuǎn)移相關(guān)免疫細(xì)胞的研究策略幾乎在所有腫瘤中都能找到巨噬細(xì)胞的蹤影。這些腫瘤相關(guān)巨噬細(xì)胞通過分泌細(xì)胞因子、趨化因子和基質(zhì)蛋白酶等重塑微環(huán)境,促進(jìn)腫瘤的生長、侵襲和轉(zhuǎn)移[38]。相對于其他免疫細(xì)胞,TAMs參與腫瘤轉(zhuǎn)移各個(gè)階段的機(jī)制研究相對比較明確[39]。同時(shí)有研究證實(shí)TAMs會影響腫瘤治療結(jié)果[40]。研究發(fā)現(xiàn)多烯紫杉醇可以殺滅具有免疫抑制功能的TAMs,同時(shí)誘導(dǎo)抗腫瘤髓性細(xì)胞的增加[41]。所以,針對TAMs設(shè)計(jì)干預(yù)藥物治療腫瘤已成為研究熱點(diǎn)。

基于TAMs在腫瘤疾病過程中的重要作用和分子機(jī)制,已研發(fā)出一些相關(guān)藥物。目前的策略是:(1) 清除TAMs; (2) 對TAMs進(jìn)行再馴化,剝離促癌功能,保留正常功能[42]。基于完全清除的策略,與TAMs生存密切相關(guān)的CSF-1/CSF-1R必定成為研究熱點(diǎn)。在美國的臨床研究注冊網(wǎng)站(https://clinicaltrials.gov)上已經(jīng)可以找到多項(xiàng)關(guān)于CSF-1抑制劑與化療聯(lián)合的臨床研究。在乳腺癌小鼠模型中,運(yùn)用CSF-1R抑制劑和紫杉醇聯(lián)合應(yīng)用,可以顯著抑制具有免疫抑制功能的TAMs,從而提高CD8+T細(xì)胞的殺傷作用,進(jìn)而顯著提高紫杉醇的治療效果[43]。人CSF-1R特異性單克隆抗體 (RG7155)已經(jīng)進(jìn)入I期臨床試驗(yàn),用于治療彌漫性巨細(xì)胞瘤[44-45],且已有患者從中獲益。但是在抑制CSF-1R時(shí),除了TAMs會被清除,非TAMs也會被清除,而且抑制了CSF-1R后有可能增加PD1和CTLA-4的表達(dá)。是否可以只清除TAMs呢？研究發(fā)現(xiàn)在絕大多數(shù)腫瘤中TAMs的募集必須依賴CCL2。通過抑制CCL2-CCLR2通路可以明顯減少TAMs數(shù)量。通過抗體介導(dǎo)的CCL2抑制,可以明顯抑制單核細(xì)胞募集到原位乳腺癌和肺轉(zhuǎn)移的乳腺癌,導(dǎo)致腫瘤生長受抑,患者獲益[46-47]。但是這樣會導(dǎo)致腫瘤細(xì)胞代償性分泌CCL2,同時(shí)抑制單核細(xì)胞募集,骨髓中滯留了大量單核細(xì)胞,一旦停藥,腫瘤生長會迅速反彈[46]。清除TAMs的策略會產(chǎn)生許多不良反應(yīng),因此對腫瘤細(xì)胞進(jìn)行再訓(xùn)化已然成為一種可選的策略。通過再訓(xùn)化增加巨噬細(xì)胞的抗腫瘤能力,同時(shí)降低其促腫瘤能力。研究發(fā)現(xiàn),在小鼠乳腺癌模型中抑制IL10通路,可以顯著提高化療效果[48]。

巴維昔單抗 (Bavituximab)是一種具有臨床應(yīng)用前景的免疫藥物,可靶向作用于磷脂酰絲氨酸。而在腫瘤患者化療后,磷脂酰絲氨酸會暴露腫瘤新生血管內(nèi)皮細(xì)胞,因此使用巴維昔單抗能有效阻斷血管新生,延緩腫瘤轉(zhuǎn)移。將巴維昔單抗與化療藥物聯(lián)用,在非小細(xì)胞肺癌患者中進(jìn)行Ⅱ期臨床試驗(yàn),發(fā)現(xiàn)兩者聯(lián)用的效果是單用化療藥物的 2 倍,且無進(jìn)展生存期和總體生存趨勢提高50%[49]。針對Ⅱ期或Ⅲ期直腸腺癌及HER2陰性的乳腺癌患者的臨床試驗(yàn)也相繼提上日程[50]。在動(dòng)物實(shí)驗(yàn)中發(fā)現(xiàn)巴維昔單抗可以從多層面再激活已 “沉睡”的抗腫瘤免疫功能,包括促TAMs的M1型轉(zhuǎn)化、抑制腫瘤相關(guān)MDSCs活化招募及參與樹突狀細(xì)胞向功能性抗原提呈細(xì)胞轉(zhuǎn)化等,提示巴維昔單抗具有良好的臨床應(yīng)用前景[49,51-52]。

結(jié)語除了TAMs以外,機(jī)體內(nèi)還有許多細(xì)胞參與腫瘤的進(jìn)程,在有效認(rèn)識各種細(xì)胞相關(guān)作用的前提下,針對某一特定細(xì)胞的功能進(jìn)行藥物設(shè)計(jì)是當(dāng)下主流的干預(yù)思路。機(jī)體是一個(gè)整體,體內(nèi)環(huán)境在不斷變化,我們認(rèn)為今后腫瘤免疫治療的策略應(yīng)該針對多種細(xì)胞參與的多個(gè)靶點(diǎn)進(jìn)行干預(yù)以及調(diào)動(dòng)機(jī)體免疫功能。

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The metastasis-promoting roles of tumor-infiltrating immune cells and potential therapeutic strategies

LUO Qin1,SHAO Wei-qing2,3,YANG Lu-yu2,3,YU Guang-yang1,QIN Lun-xiu1,2,3△

(1InstituteofBiomedicalSciences,FudanUniversity,Shanghai200032,China;2DepartmentofGeneralSurgery,HuashanHospital,Shanghai200040,China;3CancerMetastasisInstitute,FudanUniversity,Shanghai200040,China)

【Abstract】Tumor metastasis is mainly responsible for cancer mortality.It is promoted by both accumulation of intrinsic alterations and interaction of cancer cells with various stromal cells in tumor microenvironment.Tumor-infiltrating immune cells including tumor-associated macrophages (TAMs),myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Treg),have been shown to support immune suppression and the metastasis of tumor cells.The dissemination of tumor cells to distant organ sites necessitates a treacherous journey,which requires immune escape,pre-metastatic niche formation,tumor cell egress into blood circulation finally arrival at the target organ and persistent metastatic growth.Each step of tumor metastasis is fostered by the communication between tumor and immune cells.This review focuses on the interactions between tumor cells and tumor-infiltrating immune cells,and potential immune strategies.

【Key words】tumor metastasis;immune cells;targeting pro-metastatic immune cells

【中圖分類號】R 392.12; R 730

【文獻(xiàn)標(biāo)識碼】B

doi:10.3969/j.issn.1672-8467.2016.01.019

(收稿日期:2015-11-06;編輯:段佳)

△Corresponding authorE-mail:qinlx@fudan.edu.cn