韓雪綜述， 黃金華審校

(中山大學(xué)腫瘤防治中心微創(chuàng)介入科，華南腫瘤學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室， 廣州 510060)

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PD-1/PD-L1在肝細(xì)胞癌治療中的研究進(jìn)展*

韓雪綜述， 黃金華△審校

(中山大學(xué)腫瘤防治中心微創(chuàng)介入科，華南腫瘤學(xué)國(guó)家重點(diǎn)實(shí)驗(yàn)室， 廣州 510060)

肝細(xì)胞癌(簡(jiǎn)稱肝癌)起病隱匿，進(jìn)展迅速，容易復(fù)發(fā)和轉(zhuǎn)移。較長(zhǎng)一段時(shí)間以來(lái)，傳統(tǒng)的治療手段難以進(jìn)一步提高肝癌病人的預(yù)后，而免疫治療被認(rèn)為是最有希望解決這一難題的新型療法。免疫檢查點(diǎn)是腫瘤免疫逃逸的主要機(jī)制之一。其中，PD-1/PD-L1是抗腫瘤免疫治療的重要靶點(diǎn)。近年來(lái)，基于PD-1/PD-L1信號(hào)通路的免疫療法在實(shí)體腫瘤或血液系統(tǒng)惡性腫瘤中顯示出令人振奮的抗腫瘤作用。本文對(duì)PD-1/PD-L1在肝癌治療中的相關(guān)研究進(jìn)行綜述，探討PD-1/PD-L1阻斷在肝癌治療中的應(yīng)用前景。

肝細(xì)胞癌；PD-1/PD-L1；免疫檢查點(diǎn)；免疫治療

原發(fā)性肝癌是最常見(jiàn)的惡性腫瘤之一,其發(fā)病率居我國(guó)惡性腫瘤第5位、死亡率居第3位，其中肝細(xì)胞癌(簡(jiǎn)稱肝癌)占70%～90%[1-2]。目前肝癌的治療策略主要是包括手術(shù)、放療、全身化療、靶向治療和微創(chuàng)介入治療在內(nèi)的綜合治療，但仍難以突破肝癌治療后高轉(zhuǎn)移率和高復(fù)發(fā)率的瓶頸。近年來(lái)，隨著對(duì)腫瘤微環(huán)境研究的深入，研究者們發(fā)現(xiàn)在肝癌的發(fā)生與發(fā)展過(guò)程中，大量基因突變的累積導(dǎo)致多種抗原產(chǎn)生，可被免疫系統(tǒng)識(shí)別并特異性地殺傷[3]。但同時(shí)肝癌細(xì)胞通過(guò)多種機(jī)制逃避機(jī)體的免疫監(jiān)控，并與肝臟內(nèi)的免疫細(xì)胞和炎癥因子相互作用，在腫瘤內(nèi)部形成獨(dú)特的免疫微環(huán)境。

1 肝癌的免疫微環(huán)境

肝臟本身是一個(gè)重要的免疫器官，是清除血液中腸道來(lái)源病原菌的第一道防線[4-6]。肝臟通過(guò)多種免疫細(xì)胞及時(shí)有效地識(shí)別、活化、清除病原體，同時(shí)又通過(guò)精確的平衡調(diào)節(jié)，防止過(guò)度炎癥反應(yīng)對(duì)機(jī)體造成損害[4]。在維持肝臟內(nèi)環(huán)境穩(wěn)態(tài)的過(guò)程中，肝竇內(nèi)皮細(xì)胞(liver sinusoidal endothelial cell,LSEC)、肝巨噬細(xì)胞(kupffer cell,KC)、樹(shù)突狀細(xì)胞(dentritic cell,DC) 和肝臟固有淋巴細(xì)胞發(fā)揮重要的免疫調(diào)節(jié)功能[7]。然而在腫瘤負(fù)荷狀態(tài)下，這一平衡被打破(圖1)。研究證實(shí)，持續(xù)的病毒感染和腫瘤新生抗原刺激使肝臟內(nèi)形成免疫抑制狀態(tài)，對(duì)肝癌的形成和進(jìn)展起促進(jìn)作用[8-9]。在肝癌組織中具有免疫抑制功能的細(xì)胞群體如調(diào)節(jié)性T細(xì)胞(regulatory T cell,Treg)、骨髓抑制細(xì)胞(myeloid-derived suppressor cell,MDSC)明顯增加[10-14]。腫瘤內(nèi)CD8+T細(xì)胞是監(jiān)控和殺傷腫瘤細(xì)胞的主要免疫細(xì)胞，肝癌微環(huán)境通過(guò)多種方式抑制CD8+T細(xì)胞的功能。肝癌患者體內(nèi)分離的Treg可以抑制CD8+T細(xì)胞的增殖分化以及產(chǎn)生穿孔素的功能[15]。MDSC通過(guò)分泌抑制性細(xì)胞因子白細(xì)胞介素10(interleukin-10, IL-10)和激活Treg間接抑制CD8+ T細(xì)胞[16]。同時(shí)MDSC還通過(guò)抑制DC細(xì)胞的功能削弱腫瘤的抗原呈遞[14]。DC是專職的抗原遞呈細(xì)胞，能將腫瘤抗原呈遞給初始T細(xì)胞并激活抗腫瘤免疫。而在肝癌患者體內(nèi)可檢測(cè)到一群分化抗原簇14 (cluster of differentiation 14,CD14) 陽(yáng)性、細(xì)胞毒性T淋巴細(xì)胞相關(guān)抗原4(cytotoxic T-lymphocyte antigen-4, CTLA-4) 陽(yáng)性的DC，通過(guò)分泌免疫抑制性細(xì)胞因子IL-10和吲哚胺-2,3-雙加氧酶(indoleamine-2, 3-dioxygenase,IDO)抑制T細(xì)胞免疫應(yīng)答[17]。此外，抗原的持續(xù)暴露使腫瘤特異性淋巴細(xì)胞表面過(guò)度表達(dá)CTLA-4、程序性死亡蛋白1 (programmed cell death 1，PD-1)和淋巴細(xì)胞活化基因-3 (lymphocyte activation gene-3,LAG-3)共抑制信號(hào)分子，最終使T細(xì)胞處于無(wú)免疫應(yīng)答的失能狀態(tài)[18-19]。肝癌的腫瘤微環(huán)境中各種免疫細(xì)胞及其分泌因子、趨化因子和細(xì)胞外基質(zhì)(extracellular matrix，ECM)等非細(xì)胞成分均可能參與肝癌的形成[20]。因此針對(duì)肝癌內(nèi)免疫抑制機(jī)制、扭轉(zhuǎn)T細(xì)胞的失能狀態(tài)，使T細(xì)胞重新激活并發(fā)揮抗腫瘤作用是肝癌免疫治療的一個(gè)重要方向。

圖1 肝癌的抑制性免疫微環(huán)境

正常肝臟內(nèi)環(huán)境穩(wěn)態(tài)由肝細(xì)胞、間質(zhì)細(xì)胞(LESC、KC、DC)和淋巴細(xì)胞(CD4+T、CD8+T)等共同維持。肝癌內(nèi)微環(huán)境失衡，抑制性免疫細(xì)胞(Treg、MDSC)明顯增加。T細(xì)胞通過(guò)T細(xì)胞受體(T-cell receptor，TCR)/主要組織相容性復(fù)合物(major histocompability complex，MHC)途徑識(shí)別腫瘤抗原，而腫瘤細(xì)胞(tumor cell)、Treg、MDSC、DC可通過(guò)PD-L1/PD-1、分泌細(xì)胞因子等方式抑制T細(xì)胞的功能。

2 PD-1/PD-L1作用機(jī)制

PD-1屬于CD28超家族成員，與配體程序性死亡配體-1(programmed death-ligand 1,PD-L1)或者程序性死亡配體-2(programmed death-ligand 2,PD-L2)結(jié)合后向T細(xì)胞受體(T-cell receptor，TCR)傳遞共抑制信號(hào)[21-22]。PD-1主要表達(dá)于活化的T細(xì)胞表面，也可表達(dá)于B細(xì)胞、Treg細(xì)胞、自然殺傷細(xì)胞(natural killer cell ,NK)和MDSC。其配體 PD-L1 和 PD-L2主要表達(dá)于巨噬細(xì)胞、單核細(xì)胞等多種炎性細(xì)胞[22-23]。除了免疫細(xì)胞，腫瘤細(xì)胞表面亦可表達(dá)PD-1配體,如黑色素瘤、腎細(xì)胞癌、膀胱癌和非小細(xì)胞肺癌等[24-28]。

T細(xì)胞的活化需要兩個(gè)信號(hào)，第一信號(hào)來(lái)自TCR和抗原的特異性結(jié)合，第二信號(hào)來(lái)自CD80/CD28等輔助分子的激活[29]。當(dāng)位于T細(xì)胞表面的PD-1和配體結(jié)合，PD-1胞質(zhì)區(qū)的免疫受體酪氨酸活化基序(immunoreceptor tyrosine switch motifs,ITSM)結(jié)構(gòu)域中的酪氨酸發(fā)生磷酸化，募集含兩個(gè)SH結(jié)構(gòu)的蛋白酪氨酸磷酸酶(SH2 domain-containing protein-tyrosine phosphatase-2，SHP-2)，使TCR和CD28下游的ζ鏈相關(guān)蛋白激酶70和磷脂酰肌醇3激酶發(fā)生去磷酸化，從而阻斷T細(xì)胞的激活[30]。

PD-1可以在炎性介質(zhì)，如干擾素γ(interferon-γ，IFN-γ)作用下誘導(dǎo)性表達(dá)。IFN-γ可以誘導(dǎo)干擾素調(diào)節(jié)因子9(interferon regulatory factor 9,IRF-9)結(jié)合于PD-1基因啟動(dòng)子，引起T細(xì)胞對(duì)PD-1進(jìn)行轉(zhuǎn)錄 。同時(shí)，IFN-γ的刺激還可以上調(diào)細(xì)胞表面的PD-L1表達(dá)[31-32]。在腫瘤微環(huán)境中， T 細(xì)胞識(shí)別腫瘤抗原后活化擴(kuò)增為效應(yīng)T細(xì)胞，特異性地殺傷腫瘤細(xì)胞，并分泌大量炎性因子如IFN-γ；活化后的T 細(xì)胞開(kāi)始表達(dá) PD-1，長(zhǎng)時(shí)間抗原刺激引起T細(xì)胞過(guò)度表達(dá)PD-1，導(dǎo)致T細(xì)胞失能[33]。多數(shù)腫瘤細(xì)胞通過(guò)這種方式逃避免疫細(xì)胞的攻擊[23-34]。因此使用阻斷劑阻斷 PD-1 和 PD-L1 間的相互作用，可恢復(fù) T 細(xì)胞的活性和殺傷腫瘤細(xì)胞的能力，這是目前臨床治療中使用PD-1/PD-L1抗體進(jìn)行免疫治療的理論依據(jù)。

3 PD-1/PD-L1在肝癌治療中的臨床前研究

上調(diào)免疫檢查點(diǎn)分子表達(dá)(如PD-1、PD-L1、CTLA-4、LAG-3等)是肝癌逃避免疫監(jiān)視的重要機(jī)制之一[35]。這些免疫檢查點(diǎn)均可作為免疫治療的靶點(diǎn)，其中以PD-1/PD-L1的研究最受關(guān)注。在肝癌微環(huán)境中，PD-L1在腫瘤細(xì)胞和其周?chē)拈g質(zhì)細(xì)胞(LESC、KC、腫瘤相關(guān)巨噬細(xì)胞)表面表達(dá)均明顯升高[36-38]。在針對(duì)肝癌組織中PD-1及其配體表達(dá)情況的研究中，Wang等[39]對(duì)26例中國(guó)肝癌患者腫瘤標(biāo)本進(jìn)行免疫組化染色，發(fā)現(xiàn)PD-1多集中于免疫細(xì)胞浸潤(rùn)區(qū)域。PD-L1和PD-L2分散或局部地表達(dá)于24/26(92.3%)和 23/26(88.5%)例標(biāo)本中。法國(guó)的Calderaro等[40]分析了217例肝癌患者PD-L1在肝癌組織中的表達(dá)與臨床病理學(xué)特征和免疫組化標(biāo)志物的關(guān)系。結(jié)果顯示,肝癌組織中PD-L1的高表達(dá)與腫瘤侵襲性呈正相關(guān)。同時(shí), 腫瘤局部浸潤(rùn)的炎癥細(xì)胞高表達(dá)的PD-L1與血清AFP水平、大血管侵犯、分化程度以及腫瘤組織學(xué)亞型也成正相關(guān)。來(lái)自韓國(guó)的一項(xiàng)研究[41]將85例肝癌手術(shù)切除腫瘤組織中PD-L1和PD-L2的表達(dá)分別進(jìn)行預(yù)后分析，二者的表達(dá)均與肝癌患者的預(yù)后成負(fù)相關(guān)，且多因素分析顯示PD-L1是獨(dú)立的預(yù)后因素。因此，PD-L1的表達(dá)增高見(jiàn)于肝癌細(xì)胞和局部炎癥細(xì)胞，可提示更高度惡性的腫瘤生物學(xué)行為，往往與更差的預(yù)后相關(guān)。

在侵襲性轉(zhuǎn)基因肝癌小鼠的治療研究中，抗PD-L1抗體與共刺激分子激動(dòng)劑(抗CD137和抗CD252抗體)聯(lián)合，可以逆轉(zhuǎn)小鼠體內(nèi)的免疫抑制狀態(tài)，延長(zhǎng)小鼠生存時(shí)間[42]。人工構(gòu)建僅表達(dá)PD-1胞外段的真核質(zhì)粒，可產(chǎn)生可溶性PD-1(soluble PD-1,sPD-1),能夠以高親和力與PD-L1結(jié)合，發(fā)揮PD-L1抗體作用。IL-12與sPD-1聯(lián)合治療H22肝癌小鼠，可通過(guò)增強(qiáng)CD8+T細(xì)胞的細(xì)胞毒性，上調(diào)促炎癥因子IFN-γ和IL-2，下調(diào)免疫抑制性細(xì)胞因子IL-10，增強(qiáng)小鼠的抗腫瘤免疫[43]。在另外一項(xiàng)聯(lián)合治療的研究中，CD184抑制劑、索拉非尼和PD-L1抗體聯(lián)合治療肝癌模型小鼠，亦可增強(qiáng)CD8+T細(xì)胞的特異性抗腫瘤免疫應(yīng)答[44]。射頻消融(radiofrequency ablation，RFA)是常用的肝癌局部治療手段，主要通過(guò)高頻射頻波使組織中離子震蕩產(chǎn)熱，達(dá)到滅活腫瘤的目的。在腫瘤組織發(fā)生凝固性壞死的同時(shí)，大量腫瘤細(xì)胞碎片可被免疫細(xì)胞識(shí)別并激活特異性抗腫瘤免疫[45]。Shi等[46]對(duì)雙側(cè)荷瘤的CT26小鼠進(jìn)行單側(cè)消融治療，觀察到對(duì)側(cè)腫瘤生長(zhǎng)受到短暫抑制。當(dāng)聯(lián)合PD-1抗體治療后，小鼠對(duì)側(cè)腫瘤生長(zhǎng)得到持續(xù)控制，生存期顯著延長(zhǎng)。經(jīng)研究發(fā)現(xiàn)，射頻消融可激活全身性免疫反應(yīng)，未消融側(cè)腫瘤內(nèi)CD8+T細(xì)胞增加，且消融后期T細(xì)胞表面PD-1上調(diào)。因此，PD-1/PD-L1阻斷治療可以進(jìn)一步增強(qiáng)RFA引起的抗腫瘤免疫應(yīng)答，二者聯(lián)合具有協(xié)同作用。這將會(huì)是較有前景的肝癌治療策略，為治療肝癌遠(yuǎn)處轉(zhuǎn)移提供新思路。

4 PD-1/PD-L1在肝癌治療中的案例報(bào)道和臨床研究

抗PD-1/PD-L1抗體治療肝癌的個(gè)案報(bào)道目前較少。有1例來(lái)自德國(guó)[47]，患者為有丙型肝炎病史的73歲女性，腫瘤分期為巴塞羅那肝癌分期D期?；颊咝袃芍?次的PD-1阻斷劑Nivolumab靜脈注射治療，治療4個(gè)周期后獲得腫瘤完全應(yīng)答(complete response，CR)(改良的實(shí)體瘤療效評(píng)價(jià)標(biāo)準(zhǔn))。治療過(guò)程中病毒載量下降(655 000 IE/ml降至107 000 IE/ml)，AFP恢復(fù)正常。但由于四肢嚴(yán)重的皮疹反應(yīng)，患者在治療6個(gè)周期后停止治療，并于第6個(gè)月死于肝衰竭。另1例來(lái)自美國(guó)[48]，患者為患有劍突下轉(zhuǎn)移性肝癌的75歲男性，原發(fā)腫瘤切除術(shù)后。該患者在5個(gè)月的索拉非尼治療無(wú)效后進(jìn)行PD-1阻斷劑Pembrolizumab治療，治療6個(gè)周期后劍突下腫塊明顯縮小(8cm ×6cm縮小至4cm×1.6cm)，同時(shí)伴有AFP顯著下降(8 877ng/mL降至1.7ng/mL)。該患者對(duì)Pembrolizumab完全耐受，無(wú)治療相關(guān)不良反應(yīng)。盡管成功案例尚少，抗PD-1/PD-L1治療仍為傳統(tǒng)治療方法無(wú)效的患者帶來(lái)了新的希望。

目前多個(gè)抗PD-1/PD-L1治療肝癌的臨床研究正在進(jìn)行中，參與研究的PD-1/ PD-L1阻斷劑主要有Nivolumab(BMS-936558)、CT-011(Pidilizumab) 和MEDI4736等，其中Nivolumab在晚期肝癌的臨床研究中最為常見(jiàn)(表1)。

PD-1阻斷劑Nivolumab是人源化IgG4單克隆抗體，通過(guò)阻斷PD-1/PD-L通路來(lái)恢復(fù)T細(xì)胞的抗腫瘤能力[49]。2016年9月11日，Sangro等[50]在國(guó)際肝癌協(xié)會(huì)會(huì)議公布了Nivolumab治療晚期肝癌安全性和抗腫瘤效力的Ⅰ/Ⅱ期非隨機(jī)臨床研究(NCT01658878)的近期結(jié)果：該研究目前共納入了214例無(wú)手術(shù)及局部治療指征或治療后進(jìn)展的晚期肝癌患者。患者接受Nivolumab靜脈注射的劑量為3mg/kg，兩周一次。有35例患者出現(xiàn)應(yīng)答，其中33例達(dá)到部分應(yīng)答(94%)，2例達(dá)到完全應(yīng)答(6%)； 另外111例患者出現(xiàn)疾病穩(wěn)定(52%)。根據(jù)實(shí)體瘤診斷標(biāo)準(zhǔn)RECISTv1.1，患者客觀反應(yīng)率為16%；疾病控制率達(dá)68%；6個(gè)月生存率82.5%，9個(gè)月生存率70.8%。常見(jiàn)的治療相關(guān)副作用主要包括：乏力(21%)、瘙癢(15%)和皮疹(12%)。治療過(guò)程中有7%的患者因無(wú)法耐受藥物毒性而終止治療。該項(xiàng)早期臨床研究給我們帶來(lái)了振奮人心的初步結(jié)果，Nivolumab單藥治療在晚期肝癌患者中安全可控，部分患者可出現(xiàn)早期、持續(xù)的應(yīng)答，且與是否患有肝炎、PD-L1的表達(dá)量無(wú)關(guān)。

表1 肝癌中抗PD-1/PD-L1治療臨床研究

PD-1/PD-L1阻斷是否能夠成為肝癌治療的一線方案，針對(duì)這一問(wèn)題，Nivolumab對(duì)比索拉非尼一線治療晚期肝癌的III期臨床試驗(yàn)(NCT02576509)目前正在進(jìn)行當(dāng)中。然而，另外一項(xiàng)抗PD-1單克隆抗體Pidilizumab(CT-011)的Ⅰ期臨床試驗(yàn)(NCT00966251)由于進(jìn)行過(guò)程中未觀察到明顯的臨床獲益而提前終止。近年來(lái)，多個(gè)臨床研究開(kāi)展探索Nivolumab與其他藥物如轉(zhuǎn)化生長(zhǎng)因子β (transforming growth factor β,TGF-β),受體激酶阻斷劑Galunisertib(LY2157299)、殺傷細(xì)胞免疫球樣受體KIR 阻斷劑Lirilumab等聯(lián)合治療肝癌的策略。PD-L1阻斷劑MEDI4736是人源化IgG1單克隆抗體[51]，MEDI4736單獨(dú)(NCT01938612)或聯(lián)合抗CTLA-4單抗Tremelimumab治療肝癌的早期臨床試驗(yàn)(NCT02519348)均在招募中。

5 展 望

隨著對(duì)肝癌免疫治療研究的逐步深入，越來(lái)越多的結(jié)果提示我們，肝癌的免疫抑制機(jī)制具有多樣性和復(fù)雜性，單一的治療手段往往難以解決問(wèn)題。近年來(lái)PD-1/PD-L1抗體在晚期黑色素瘤和非小細(xì)胞肺癌等多種腫瘤治療中顯示出了較好的療效，但抗PD-1/PD-L1治療能否成為肝癌有效的免疫治療手段，還需通過(guò)進(jìn)一步臨床研究加以證明。未來(lái)，抗PD-1/PD-L1治療應(yīng)當(dāng)與化療、靶向治療、局部治療等傳統(tǒng)的治療策略以及其他免疫治療方法相結(jié)合，在利用綜合治療協(xié)同作用的同時(shí)減少傳統(tǒng)治療手段帶來(lái)的肝臟損害，為肝癌治療帶來(lái)新的突破。

作者聲明：本文第一作者對(duì)于研究和撰寫(xiě)的論文出現(xiàn)的不端行為承擔(dān)相應(yīng)責(zé)任；

利益沖突：本文全部作者均認(rèn)同文章無(wú)相關(guān)利益沖突；

學(xué)術(shù)不端：本文在初審、返修及出版前均通過(guò)中國(guó)知網(wǎng)(CNKI)科技期刊學(xué)術(shù)不端文獻(xiàn)檢測(cè)系統(tǒng)學(xué)術(shù)不端檢測(cè)；

同行評(píng)議：經(jīng)同行專家雙盲外審，達(dá)到刊發(fā)要求。

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The Research Progress of PD-1/PD-L1 in the Treatment of Hepatocellular Carcinoma*

Han Xue, Huang Jinhua△

(DepartmentofMinimallyInvasiveInterventionalRadiology,SunYat-senUniversityCancerCenter,StateKeyLaboratoryofOncologyinSouthChina,Guangzhou510060,Guangdong,China)

Hepatocellular carcinoma(HCC)is a malignancy with insidious onset, rapid progress, high recurrence and metastasis rate. Traditional treatment is difficult to further improve the prognosis of patients with HCC for a long time, and immunotherapy is considered to be the most promising therapeutic approach to solve this problem. Immune checkpoint is one of the main mechanisms of tumor immune evasion. PD-1/PD-L1 is an important target for anti-tumor immunotherapy among these checkpoints. Recently, agents targeting the PD-1/PD-L1 pathway were shown to display impressive antitumor activity in various solid or hematological malignancies. In this review we summarize the relative studies on HCC and discuss the potential of PD-1/PD-L1 blockade in HCC therapy.

HCC; PD-1/PD-L1; Immune Checkpoints; Immunotherapy

2017- 02- 07

2017- 03- 15

*國(guó)家自然科學(xué)基金(編號(hào)：81371652)；中山大學(xué)臨床醫(yī)學(xué)研究5010計(jì)劃項(xiàng)目(編號(hào)：2016002)

韓雪(1990-)，女，碩士研究生，主要從事腫瘤介入與免疫治療研究。

△黃金華，主任醫(yī)師，博士生導(dǎo)師，E-mail：huangjh@sysucc.org.cn

R735.7；R730.51

A

10.3969/j.issn.1674- 0904.2017.02.011