施敬瑤 張海洋 陳公琰▲
1.哈爾濱醫(yī)科大學(xué)附屬腫瘤醫(yī)院內(nèi)一科,黑龍江哈爾濱150081;
2.哈爾濱醫(yī)科大學(xué)附屬腫瘤醫(yī)院泌尿外科,黑龍江哈爾濱150081
PD-1/PD-L1信號(hào)通路在實(shí)體瘤中的研究進(jìn)展
施敬瑤1張海洋2陳公琰1▲
1.哈爾濱醫(yī)科大學(xué)附屬腫瘤醫(yī)院內(nèi)一科,黑龍江哈爾濱150081;
2.哈爾濱醫(yī)科大學(xué)附屬腫瘤醫(yī)院泌尿外科,黑龍江哈爾濱150081
近年來,PD-1/PD-L1信號(hào)通路因參與腫瘤免疫逃逸而成為研究熱點(diǎn),PD-1/PD-L1信號(hào)通路的激活有助于腫瘤細(xì)胞的免疫逃逸。體內(nèi)外實(shí)驗(yàn)證實(shí),阻斷該通路可增強(qiáng)機(jī)體內(nèi)源性抗腫瘤免疫效應(yīng)。PD-1及其配體PDL1的表達(dá)不僅與患者的臨床分期及預(yù)后相關(guān),還有可能成為臨床生物標(biāo)志物,而成為腫瘤免疫治療的新靶點(diǎn)。目前,PD-1/PD-L1信號(hào)通路抑制劑已進(jìn)入臨床試驗(yàn)階段,并且在治療多種實(shí)體瘤中具有良好的療效和安全性。
PD-1/PD-L1信號(hào)通路;實(shí)體瘤;研究進(jìn)展
程序性死亡因子1及其配體(PD-1/PD-L1)是一對(duì)免疫共刺激因子。正常情況下,PD-1通過其配體PD-L1發(fā)揮免疫調(diào)控作用。近年來,PD-1及其配體PD-L1因其參與腫瘤免疫逃逸機(jī)制而受到關(guān)注。PD-1/ PD-L1信號(hào)通路的激活可導(dǎo)致免疫抑制性腫瘤微環(huán)境形成,使腫瘤細(xì)胞逃避機(jī)體免疫監(jiān)視和殺傷,而阻斷PD-1/PD-L1信號(hào)通路可逆轉(zhuǎn)腫瘤免疫微環(huán)境,增強(qiáng)內(nèi)源性抗腫瘤免疫效應(yīng)[1]。也有研究認(rèn)為,腫瘤細(xì)胞是通過上調(diào)PD-L1的表達(dá)來逃避T細(xì)胞的識(shí)別[2]。國內(nèi)外多項(xiàng)研究證明,PD-1及PD-L1的表達(dá)不僅能反映患者的臨床分期和生存率,并有望成為腫瘤免疫治療的新靶點(diǎn)。本文就其在實(shí)體腫瘤中的研究進(jìn)展進(jìn)行綜述。
PD-1又稱CD279,是一種相對(duì)分子量為55 000~60 000的Ⅰ型跨膜蛋白,屬免疫球蛋白超家族成員。PD-1主要表達(dá)于活化的CD4+T細(xì)胞、CD8+T細(xì)胞、B細(xì)胞、NK細(xì)胞、單核細(xì)胞和樹突狀細(xì)胞等免疫細(xì)胞上,促進(jìn)T細(xì)胞的成熟[3]。PD-1的配體屬B7家族成員,包括PD-L1(又名B7-H1,CD274)和PD-L2(又名B7-DC),兩者均高表達(dá)于胎盤組織;低表達(dá)于脾臟、淋巴結(jié)、胸腺;腦組織中無表達(dá)。其中,PD-L1同是Ⅰ型跨膜蛋白,主要表達(dá)于抗原提呈細(xì)胞、B細(xì)胞、T細(xì)胞、上皮細(xì)胞、肌細(xì)胞、內(nèi)皮細(xì)胞及各種腫瘤細(xì)胞,并參與腫瘤相關(guān)的免疫反應(yīng)。PD-1及PD-L1共同組成PD-1/PD-L1信號(hào)通路,抑制生長因子的生成和細(xì)胞增殖,并對(duì)T細(xì)胞的活化及調(diào)控免疫應(yīng)答起到重要作用。PD-L1不僅對(duì)T細(xì)胞的活化起到重要作用,而且還可抑制T細(xì)胞介導(dǎo)的免疫應(yīng)答,有助于腫瘤細(xì)胞逃避機(jī)體免疫系統(tǒng)的識(shí)別和殺傷[4]。在健康的機(jī)體中,PD-1/PD-L1信號(hào)通路的激活可減少免疫反應(yīng)對(duì)周圍組織的損傷,避免發(fā)生自身免疫疾病[3-5]。另一方面,該通路的激活又可降低腫瘤局部微環(huán)境T細(xì)胞的免疫效應(yīng),從而介導(dǎo)腫瘤免疫逃逸,促進(jìn)癌癥的進(jìn)展[1]。
目前公認(rèn)的腫瘤的免疫逃避機(jī)制主要包括以下幾個(gè)方面:①抗原調(diào)變和抗原缺失;②腫瘤細(xì)胞的漏逸;③腫瘤細(xì)胞表面的MHCI類分子表達(dá)低下;④腫瘤細(xì)胞導(dǎo)致的免疫抑制;⑤腫瘤細(xì)胞表面缺乏共刺激信號(hào);⑥腫瘤細(xì)胞具有抗凋亡作用;⑦宿主免疫力低下等情況。而PD-1及其配體PD-L1作為一對(duì)共刺激信號(hào)主要通過以下機(jī)制產(chǎn)生作用:①PD-1與PD-L1可抑制TCR介導(dǎo)的停止信號(hào),導(dǎo)致T細(xì)胞的耐受[6]。②腫瘤細(xì)胞表達(dá)PD-L1可增加抗原特異性T細(xì)胞的調(diào)亡,因而阻斷PD-L1后可減少T細(xì)胞凋亡[7]。③最新研究表明,腫瘤微環(huán)境中的TILs的耗竭與腫瘤細(xì)胞,腫瘤來源的髓系細(xì)胞分泌的PD-L1相關(guān),阻斷PD-1/PD-L1信號(hào)通路可增加效應(yīng)性CD8+T細(xì)胞的功能,抑制Treg細(xì)胞和髓系來源抑制細(xì)胞的功能,增加抗腫瘤免疫效應(yīng)[8]。④PD-1通過下調(diào)mTOR、AKT、S6和ERK2的磷酸化及上調(diào)PTEN等基因,促進(jìn)誘發(fā)性Treg的產(chǎn)生和維持,從而發(fā)揮抑制效應(yīng)性T細(xì)胞的活性[9]。⑤選擇性抑制RAS/MEK/ERKh和PI3K/AKT信號(hào)通路,進(jìn)而抑制T細(xì)胞調(diào)亡[10]。⑥ICOS與PD-1的失衡導(dǎo)致T細(xì)胞功能異常[11]。
PD-L1高表達(dá)于各種實(shí)體惡性腫瘤,包括非小細(xì)胞肺癌、黑色素瘤、腎細(xì)胞癌、前列腺癌、乳腺癌、膠質(zhì)瘤等,其表達(dá)水平因腫瘤類型不同而不同,不僅能促進(jìn)腫瘤細(xì)胞的生長,還可誘導(dǎo)T淋巴細(xì)胞的凋亡[12]。
4.1 肺癌
近十年,PD-1/PD-L1信號(hào)通路在非小細(xì)胞肺癌中的研究不斷取得突破性進(jìn)展。但在體外實(shí)驗(yàn)中,PD-L1的作用尚無定論,各個(gè)實(shí)驗(yàn)結(jié)果相互矛盾。蔣濤等[13]應(yīng)用脂質(zhì)體轉(zhuǎn)染法將pGPU6/PD-L1(PD-L1shRNA重組質(zhì)粒)轉(zhuǎn)入A549細(xì)胞,結(jié)果顯示PD-L1的基因及蛋白表達(dá)水平均降低,不僅抑制A549細(xì)胞增殖,并可誘導(dǎo)細(xì)胞凋亡。在非小細(xì)胞肺癌中,腫瘤細(xì)胞過表達(dá)PD-L1提示侵襲性高,預(yù)后差[14-15]。而在PD-L1過表達(dá)的Ⅰ期肺腺癌患者無復(fù)發(fā)生存時(shí)間更長,與患者年齡、分期、組織類型無關(guān)[16-18]。在小細(xì)胞肺癌中,PD-L1陽性的患者總生存率高于PD-L1陰性的患者[19]。因此,PD-L1的表達(dá)如何預(yù)測患者預(yù)后尚需進(jìn)一步研究。
盡管各實(shí)驗(yàn)結(jié)果相互矛盾,但PD-1/PD-L1信號(hào)通路抑制劑作為肺癌免疫治療的新方法,其抗腫瘤療效已經(jīng)得到證實(shí)。國外臨床研究結(jié)果顯示,PD-1/PDL1信號(hào)通路抑制劑將成為癌癥免疫治療的新靶點(diǎn)[20]。Ⅰ期臨床試驗(yàn)提示僅有少數(shù)非小細(xì)胞肺癌患者對(duì)于抗PD-1抗體有效,PD-L1陽性、陰性患者的客觀緩解率分別為36%、10%,因此,PD-L1的表達(dá)可能與非小細(xì)胞肺癌免疫治療的效果相關(guān)[21]。目前,抗PD-L1抗體(Nivolumab,pembrolizumab)及抗PD-1抗體(BMS-936559、MPDL3280a、MEDI-4736)在治療非小細(xì)胞肺癌中的良好效果和安全性已得到越來越多的證實(shí)[22-23]。其中,Nivolumab和pembrolizumab已進(jìn)行Ⅲ期臨床試驗(yàn)。盡管單一應(yīng)用PD-1/PD-L1信號(hào)通路抑制劑療效確切,但動(dòng)物實(shí)驗(yàn)提示聯(lián)合用藥療效更加顯著[20]。近期研究顯示,PD-L1陽性與EGFR基因突變相關(guān)。EGFR基因突變且服用厄洛替尼或吉非替尼治療的晚期非小細(xì)胞肺癌患者中,PD-L1陽性與PD-L1陰性對(duì)比,無疾病進(jìn)展時(shí)間明顯延長。并推測EGFR信號(hào)通路的活化可能是產(chǎn)生PD-L1介導(dǎo)的腫瘤免疫逃避的原因之一。由于EGFR抑制劑導(dǎo)致PD-L1下調(diào),EGFR突變且PD-L1高表達(dá)的患者在應(yīng)用EGFR抑制劑后對(duì)吉西他濱和厄洛替尼更加敏感[24]。因此PD-L1陽性被認(rèn)為可能是潛在的抗PD-1抗體治療有效的生物學(xué)靶標(biāo)。
4.2 腎細(xì)胞癌
因腎細(xì)胞癌對(duì)傳統(tǒng)化療和放射治療均不敏感,靶向治療藥物費(fèi)用昂貴,難以在全國普及,免疫治療仍為研究熱點(diǎn)。白介素-2是近年來臨床應(yīng)用較多的細(xì)胞因子制劑。在腎細(xì)胞癌的免疫治療研究中,CTLA-4因其抑制T細(xì)胞增殖及其相應(yīng)功能而較早被研究。近十年,PD-1/PD-L1信號(hào)通路作為腫瘤免疫逃避機(jī)制的又一發(fā)現(xiàn)而成為研究熱點(diǎn)。Jilaveanu等[25]對(duì)34例腎透明細(xì)胞癌患者術(shù)后的組織進(jìn)行分析,發(fā)現(xiàn)PD-L1高表達(dá)的患者預(yù)后差;在原發(fā)病灶中,腫瘤浸潤淋巴細(xì)胞中也表達(dá)PD-L1;在腫瘤細(xì)胞或腫瘤浸潤淋巴細(xì)胞中,PD-L1的高表達(dá)與患者分期晚、生存率低、轉(zhuǎn)移快呈正相關(guān);由于原發(fā)灶和轉(zhuǎn)移灶的PD-L1表達(dá)不具有明顯的相關(guān)性,因此,在切除的腎癌組織中,PDL1的表達(dá)不能作為轉(zhuǎn)移性腎癌患者選擇PD-L1和PD-1抑制劑的理論依據(jù),且腫瘤組織內(nèi)外異質(zhì)性的存在,單部位穿刺活檢不能確定PD-L1的表達(dá)。
在治療方面,PD-1抑制劑BMS-936558因其毒性低而應(yīng)用于腎細(xì)胞癌,并取得良好效果。PD-L1抑制劑MPDL-3280A也被證明在腎細(xì)胞癌中有效[25],且PD-L1抑制劑較PD-1抑制劑療效更加明顯[26]。在非透明細(xì)胞性腎癌中,PD-L1陽性與分期晚、分級(jí)高、生存時(shí)間短相關(guān),與性別和腫瘤大小無關(guān)[27],可作為潛在的生物標(biāo)志物應(yīng)用于臨床[28]。
4.3 肝癌
目前,PD-L1在肝癌中的研究相對(duì)較少。有學(xué)者回顧性分析顯示,乙肝病毒導(dǎo)致的肝細(xì)胞癌的機(jī)制可能是通過X蛋白(HBV基因組翻譯蛋白)刺激肝細(xì)胞PD-L1的表達(dá),導(dǎo)致T細(xì)胞調(diào)亡,形成免疫抑制微環(huán)境,最終誘發(fā)肝細(xì)胞癌的形成[29]。Shi等[30]應(yīng)用流式細(xì)胞術(shù)、免疫組化等實(shí)驗(yàn)技術(shù)分別檢測58例HBV相關(guān)性肝細(xì)胞癌患者外周血及肝腫瘤組織中CD8+T淋巴細(xì)胞上PD-1的表達(dá),證明PD-1在CD8+T淋巴細(xì)胞上的表達(dá)具有負(fù)性調(diào)節(jié)CD8+T淋巴細(xì)胞活化增殖作用,其表達(dá)水平對(duì)肝細(xì)胞癌患者的病情具有預(yù)測作用,PD-1陽性且CD8+的T細(xì)胞與患者預(yù)后差及術(shù)后復(fù)發(fā)呈正相關(guān)。Qin等[31]發(fā)現(xiàn)在H22細(xì)胞中,化療藥物順鉑可使H22細(xì)胞的PD-L1表達(dá)上調(diào),其機(jī)制可能是通過Erk1/2磷酸化途徑來實(shí)現(xiàn),該學(xué)著提出化學(xué)治療與免疫治療可能共同通過ERK/MARK通路來實(shí)現(xiàn)抗腫瘤作用。
4.4 乳腺癌
在乳腺腫瘤中,因腫瘤浸潤淋巴細(xì)胞(TIL)中存在高表達(dá)的PD-1分子,故推測PD-1/PD-L1信號(hào)通路可能參與負(fù)性調(diào)控抗腫瘤相關(guān)的免疫反應(yīng)。國外學(xué)者M(jìn)uenst等[32]證實(shí),PD-1陽性高表達(dá)的腫瘤浸潤淋巴細(xì)胞不僅與腫瘤的大小、分期、淋巴轉(zhuǎn)移相關(guān),還與乳腺癌患者預(yù)后差相關(guān)。在luminal B HER2陰性、luminal B HER2陽性、ER陰性或PR陽性且HER2陽性的乳腺癌患者中,PD-L1的高表達(dá)與患者預(yù)后呈負(fù)相關(guān),此試驗(yàn)進(jìn)一步證明PD-1/PD-L1信號(hào)通路的激活可促進(jìn)腫瘤細(xì)胞逃避免疫監(jiān)視,使得腫瘤細(xì)胞繼續(xù)增殖并發(fā)生遠(yuǎn)處轉(zhuǎn)移[33]。多項(xiàng)臨床試驗(yàn)證明,PD-1和PD-L1的表達(dá)可作為評(píng)估乳腺癌預(yù)后的獨(dú)立因素,并將成為乳腺癌治療的新靶點(diǎn)[32-33]。
4.5 胃癌
在胃癌的研究中,PD-1在胃癌患者外周血CD8+T淋巴細(xì)胞表面呈高表達(dá)狀態(tài),表達(dá)率與惡性程度呈正比[34]。湯代彬[35]應(yīng)用免疫組化等技術(shù)對(duì)68例胃癌及癌周正常組織中PD-1的表達(dá)進(jìn)行檢測,并結(jié)合臨床資料進(jìn)行回顧性分析,結(jié)果顯示PD-1的表達(dá)與腫瘤浸潤深度、TNM分期、淋巴結(jié)和遠(yuǎn)處轉(zhuǎn)移相關(guān),而與患者性別、年齡、腫瘤大小、部位和病理分型無關(guān)。
但與其他部位腫瘤不同的是,PD-L1高表達(dá)的胃癌患者臨床分期較早,而臨床分期較晚的患者低表達(dá)PD-L1分子,腫瘤浸潤更深,這可能是由于長期的慢性炎癥及進(jìn)展期腫瘤的免疫逃避導(dǎo)致的,但這種猜想尚無胃癌相關(guān)的實(shí)驗(yàn)證實(shí)[36]。Sun等[37]發(fā)現(xiàn),抗人PD-L1單克隆抗體10E10可抑制與腫瘤相關(guān)的的T淋巴細(xì)胞凋亡,此項(xiàng)研究為胃癌的免疫治療提供新的理論依據(jù)。
腫瘤的免疫治療是通過激發(fā)和增強(qiáng)機(jī)體的免疫功能,以達(dá)到控制和殺滅腫瘤細(xì)胞的目的。免疫療法作為一種輔助療法與手術(shù)、化療、放療等常規(guī)療法聯(lián)合應(yīng)用。目前PD-1/PD-L1信號(hào)通路抑制劑在抗惡性腫瘤的重要作用得到廣泛重視。實(shí)驗(yàn)證明,在多種實(shí)體腫瘤中,阻滯PD-1/PD-L1信號(hào)通路均具有抗腫瘤效應(yīng)。PD-1/PD-L1抑制劑作為實(shí)體瘤免疫治療的新藥已顯示出其優(yōu)勢作用,并且也有實(shí)驗(yàn)證實(shí)聯(lián)合化療藥物使得療效更加顯著。因此,如何最大化利用PD-1/ PD-L1抑制劑抑制該信號(hào)通路股將成為未來腫瘤免疫治療的研究熱點(diǎn)。
[1]Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy[J].Nat Rev Cancer,2012,12(4):252-264.
[2]林城,陳雄,劉靜南,等.PD-1/PD-L1信號(hào)通路在非小細(xì)胞肺癌免疫逃逸及其治療中的研究進(jìn)展[J].中國肺癌雜志,2014,17(10):734-740.
[3]Keir ME,Butte MJ,F(xiàn)reeman GJ,et al.PD-1 and its ligands in tolerance and immunity[J].Annu Rev Immunol,2008,26:677-704.
[4]Saresella M,Rainone V,Al-Daghri NM,et al.The PD-1/ PD-L1 pathway in human pathology[J].Curr Mol Med,2012,12(3):259-267.
[5]KeirME,LiangSC,GuleriaI,etal.TissueexpressionofPD-L1 mediates peripheral T cell tolerance[J].J Exp Med,2006,203(4):883-895.
[6]Fife BT,Pauken KE,Eagar TN,et al.Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal[J].Nat Immunol,2009,10(11):1185-1192.
[7]Dong H,Strome SE,Salomao DR,et al.Tumor-associated B7-H1 promotes T-cell apoptosis:a potential mechanism of immune evasion[J].Nat Med,2002,8(8):793-800.
[8]Duraiswamy J,F(xiàn)reeman GJ,Coukos G.Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer[J].Cancer Res,2013,73(23):6900-6912.
[9]Francisco LM,Salinas VH,Brown KE,et al.PD-L1 regulates the development,maintenance,and function of induced regulatory T cells[J].J Exp Med,2009,206(13):3015-3029.
[10]Patsoukis N,Brown J,Petkova V,et al.Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation[J].Sci Signal,2012,5(230):a46.
[11]Sugita G,F(xiàn)ujimori M,Ikeda K.Immuno-histological andcytological examinations on distribution of newly reported co-stimulatory molecules in germinal center of human tonsils[J].Nihon Jibiinkoka Gakkai Kaiho,2005,108(1):31-37.
[12]Boland JM,Kwon ED,Harrington SM,et al.Tumor B7-H1 and B7-H3 expression in squamous cell carcinoma of the lung[J].Clin Lung Cancer,2013,14(2):157-163.
[13]蔣濤,付立業(yè),李妍.RNAi沉默肺腺癌A549細(xì)胞系PDL1基因表達(dá)對(duì)其增殖和凋亡的影響[J].現(xiàn)代腫瘤醫(yī)學(xué),2015,23(2):177-180.
[14]Mu CY,Huang JA,Chen Y,et al.High expression of PDL1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation[J].Med Oncol,2011,28(3):682-688.
[15]Chen YB,Mu CY,Huang JA.Clinical significance of programmeddeath-1ligand-1expressioninpatientswith nonsmall cell lung cancer:a 5-year-follow-up study[J].Tumori,2012,98(6):751-755.
[16]VelchetiV,SchalperKA,CarvajalDE,etal.Programmeddeath ligand-1 expression in non-small cell lung cancer[J]. Lab Invest,2014,94(1):107-116.
[17]Zhang Y,Wang L,Li Y,et al.Protein expression of programmed death 1 ligand 1 and ligand 2 independently predict poor prognosis in surgically resected lung adenocarcinoma[J].Onco Targets Ther,2014,7:567-573.
[18]YangCY,LinMW,ChangYL,etal.Programmedcelldeathligand1expressioninsurgicallyresectedstageⅠpulmonary adenocarcinoma and its correlation with driver mutations and clinical outcomes[J].Eur J Cancer,2014,50(7):1361-1369.
[19]Ishii H,Azuma K,Kawahara A,et al.Significance of programmed cell death-ligand 1 expression and its association with survival in patients with small cell lung cancer[J].J Thorac Oncol,2014,9:257-313.
[20]Topalian SL,Drake CG,Pardoll DM.Targeting the PD-1/ B7-H1(PD-L1)pathway to activate anti-tumor immunity[J].Curr Opin Immunol,2012,24(2):207-212.
[21]Brahmer JR,Tykodi SS,Chow LQ,et al.Safety and activity of anti-PD-L1 antibody in patients with advanced cancer[J].N Engl J Med,2012,366(26):2455-2465.
[22]Akbay EA,Koyama S,Carretero J,et al.Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors[J].Cancer Discov,2013,3(12):1355-1363.
[23]曹佳彬,魏敬雙.PD-1抗體在腫瘤治療中的應(yīng)用[J].中國生物制品學(xué)雜志,2014,27(6):856-860.
[24]D'Incecco A,Andreozzi M,Ludovini V,et al.PD-1 and PDL1 expression in molecularly selected non-small-cell lung cancer patients[J].Br J Cancer,2014,3(6):123-189.
[25]Jilaveanu LB,Shuch B,Zito CR,et al.PD-L1 expression in clear cell renal cell carcinoma:an analysis of nephrectomy and sites of metastases[J].J Cancer,2014,5(3):166-172.
[26]Tang PA,Heng DY.Programmed death 1 pathway inhibition in metastatic renal cell cancer and prostate cancer[J]. Curr Oncol Rep,2013,15(2):98-104.
[27]Choueiri TK,F(xiàn)ay AP,Gray KP,et al.PD-L1 expression in nonclear-cell renal cell carcinoma[J].Ann Oncol,2014,25(11):2178-2184.
[28]Harshman LC,Choueiri TK,Drake C,et al.Subverting the B7-H1/PD-1 pathway in advanced melanoma and kidney cancer[J].Cancer J,2014,20(4):272-280.
[29]吳勝昔,陳永文,朱廣倍,等.乙型肝炎病毒x基因轉(zhuǎn)染HepG2細(xì)胞后差異表達(dá)基因的篩選[J].免疫學(xué)雜志,2014,30(9):787-791.
[30]Shi F,Shi M,Zeng Z,et al.PD-1 and PD-L1 upregulation promotes CD8(+)T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients[J].Int J Cancer,2011,128(4):887-896.
[31]Qin X,Liu C,Zhou Y,et al.Cisplatin induces programmed death-1-ligand 1(PD-L1)over-expression in hepatoma H22 cells via Erk/MAPK signaling pathway[J].Cell Mol Biol(Noisy-le-grand),2010,56(Suppl):L1366-L1372.
[32]Muenst S,Schaerli AR,Gao F,et al.Expression of programmed death ligand 1(PD-L1)is associated with poor prognosis in human breast cancer[J].Breast Cancer Res Treat,2014,146(1):15-24.
[33]MuenstS,SoysalSD,GaoF,etal.Thepresenceofprogrammed death 1(PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer[J]. Breast Cancer Res Treat,2013,139(3):667-676.
[34]李超,汪宏,周勇.PD-1在胃癌患者CD8+T細(xì)胞表面的表達(dá)特點(diǎn)及臨床意義[J].胃腸病學(xué)和肝病學(xué)雜志,2011,20(5):419-422.
[35]湯代彬.程序性死亡受體PD-1在人胃癌組織中的表達(dá)及臨床意義[D].武漢:華中科技大學(xué),2010.
[36]Zheng Z,Bu Z,Liu X,et al.Level of circulating PD-L1 expression in patients with advanced gastric cancer and its clinical implications[J].Chin J Cancer Res,2014,26(1):104-111.
[37]Sun J,Xu K,Wu C,et al.PD-L1 expression analysis in gastric carcinoma tissue and blocking of tumor-associated PD-L1 signaling by two functional monoclonal antibodies[J].Tissue Antigens,2007,69(1):19-27.
Research progress of PD-1/PD-L1 pathway in solid tumors
SHI Jingyao1ZHANG Haiyang2CHEN Gongyan1▲
1.The First Department of Internal Medicine,Cancer Hospital Affiliated to Harbin Medical University,Heilongjiang Province,Harbin150081,China;2.Department of Urology Surgery,Cancer Hospital Affiliated to Harbin Medical U-niversity,Heilongjiang Province,Harbin150081,China
In recent years,PD-1/PD-L1 pathway involves the mechanism of immune escape for tumor and become a hot pot.The activation of this pathway contribute to immune escape.Experiments confirm that blocking this pathway may enhance endogenous anti-tumor immune response.The express of PD-1 and its ligand PD-L1 not only reflect the clinical stage and prognosis,but also expect to become a clinical biomarker and then it will become a new target for cancer immunotherapy.Currently,drugs blocking PD-1 and PD-L1 have entered the stage of clinical trials,which have good efficacy and safety in treatment of various solid tumors.
PD-1/PD-L1 pathway;Solid tumors;Research progress
R73[
]A[
]1673-7210淵2015冤04淵a冤-0047-04
2014-12-18本文編輯:張瑜杰)
▲通訊作者