Abstract
近年来，有关程序性死亡受体1（programmed death-1, PD-1）及其配体（programmed death-1 ligand, PD-L1）抑制剂的研究取得突破性进展，迅速改变着非小细胞肺癌（non-small cell lung cancer, NSCLC）的治疗模式。但表皮生长因子受体（epidermal growth factor receptor, EGFR）突变患者应用PD-1/PD-L1抑制剂的治疗效果并不理想。既往研究显示，肿瘤细胞PD-L1表达率与免疫抑制剂治疗效果存在相关性。但目前EGFR突变对PD-L1表达的影响并不能达成一致。我们将对相关研究进行总结，以期对基础研究或临床治疗有所帮助。
Keywords: EGFR突变, PD-1/PD-L1抑制剂, 肺肿瘤, PD-L1
Abstract
Researches on the inhibitors of programmed death-1 (PD-1) and programmed death-1 ligand (PD-L1) enjoy considerable breakthroughs in recent years, which has brought relative changes in the therapeutic model of non-small cell lung cancer (NSCLC) at an unexpected speed. However, it seems that PD-1/PD-L1 inhibitors are less effective in patients with epidermal growth factor receptor (EGFR) mutation than those without. Previous studies have shown that the expression rate of PD-L1 on tumor cells is correlated with the therapeutic effect of PD-1/PD-L1 inhibitors. Yet, there is no complete agreement on the effect of EGFR mutation on PD-L1 expression. In this review, relevant studies will be summarized with an expectation of making some contributions to basic researches and to the clinical treatment.
Keywords: EGFR mutation, PD-1/PD-L1 inhibitors, Lung neoplasms, PD-L1
肺癌，尤其是非小细胞肺癌（non-small cell lung cancer, NSCLC），是肿瘤相关性死亡的最主要原因[1]。在传统手术治疗、铂类为基础的化疗以及放疗快速发展的背景下，NSCLC的治疗效果仍不能达到理想状态。目前，以吉非替尼、厄洛替尼、奥希替尼等为代表的表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）成为存在EGFR突变NSCLC患者的标准一线治疗方案[2]，其客观缓解率可达到70%左右甚至更高，但通常1年左右就会产生耐药[3]。因此，亟待寻求新的治疗方法以应对EGFR突变的NSCLC患者耐药的发生。近年来，以程序性死亡受体1（programmed death-1, PD-1）及其配体（programmed death-1 ligand, PD-L1）抑制剂为代表的免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）在肺癌治疗中取得突破性进展，但既往研究[4-7]却显示其对EGFR突变患者的治疗效果并不理想。这就说明，EGFR突变很可能通过影响肿瘤免疫微环境，而进一步影响PD-1/PD-L1抑制剂对肿瘤的杀伤效果。PD-L1表达率是评估PD-1/PD-L1抑制剂治疗效果的潜在因素，尤其是其高表达的患者可以从相关治疗中获益更多[8]。我们将进一步总结EGFR突变对PD-L1表达影响的基础及临床研究，并对其结果存在差异的原因进行简单探讨，希望可以对相关研究及PD-1/PD-L1抑制剂的临床应用提供有效的建议及指导。
1. EGFR突变导致PD-L1表达上调相关研究
1.1. 基础研究
2014年，Azuma团队[9]对14种人NSCLC细胞系（PC9、HCC827、NCI-H1975、QG56、1-87、H1299、H2122、H322、H460、LK2、LK87、H23、A549、H157）进行流式细胞分析技术检测发现存在EGFR突变的细胞系PD-L1表达明显高于EGFR野生型细胞系（P=0.023），且EGFR突变型细胞系HCC827、PC-9、H1975可以检测到EGFR高水平的磷酸化作用（表 1）。为了探索EGFR通路对PD-L1表达的影响，研究者进一步对EGFR突变细胞系HCC827、PC-9应用厄洛替尼处理后发现其PD-L1表达下调以及EGFR磷酸化受到抑制，但对EGFR野生型细胞系A549、H1975应用厄洛替尼处理后并未影响其PD-L1的表达及EGFR磷酸化水平。该研究说明，EGFR突变可以导致人NSCLC细胞系PD-L1表达上调。
1.
依据基因突变状态和组织病理学分类的肺癌细胞系
Lung cancer cell lines classified according to oncogene status and histology
| Cell line | EGFR status | Histology |
| EGFR: epidermal growth factor receptor. | ||
| PC-9 | Del (E746-A750) | Adenocarcinoma |
| HCC827 | Del (E746-A750) | Adenocarcinoma |
| H1650 | Del (E746-A750) | Adenocarcinoma |
| 11-18 | L858R | Adenocarcinoma |
| H1975 | L858R+T790M | Adenocarcinoma |
| A549 | Wild type | Adenocarcinoma |
| H1437 | Wild type | Adenocarcinoma |
| H1573 | Wild type | Adenocarcinoma |
| H1993 | Wild type | Adenocarcinoma |
| H1944 | Wild type | Adenocarcinoma |
| H23 | Wild type | Adenocarcinoma |
| H2122 | Wild type | Adenocarcinoma |
| H322 | Wild type | Adenocarcinoma |
| LK87 | Wild type | Adenocarcinoma |
| SPC-A1 | Wild type | Adenocarcinoma |
| 1-87 | Wild type | Adenocarcinoma |
| H1299 | Wild type | Non-small cell lung cancer |
| QG56 | Wild type | Non-small cell lung cancer |
| H460 | Wild type | Large cell |
| LU-99 | Wild type | Large cell |
| LK2 | Wild type | Squamous |
| H157 | Wild type | Squamous |
| H596 | Wild type | Adenosquamous |
| Beas-2B | Wild type | Bronchiolar epithelial cell |
Chen等[10]于2015年对人NSCLC细胞系A549、PC-9、HCC827、H1975、H1993以及Beas-2B细胞系进行的相关研究进行了报道。该研究主要由四部分组成：①研究者通过蛋白质印迹法、RT-PCR检测发现，EGFR突变NSCLC细胞系（PC-9、HCC827、H1975）PD-L1表达水平明显高于EGFR野生型细胞系（A549、H1993）和Beas-2B细胞系；并进一步应用免疫组织化学染色法及流式细胞分析技术对H1975和A549细胞系PD-L1表达情况进行验证，结果与之前一致。②研究者使用了EGF去激活EGFR野生型细胞系，研究发现随着EGF激活剂量的升高（0 ng/mL-40 ng/mL）Beas-2B细胞系中p-EGFR和PD-L1蛋白表达也逐渐升高；随后，研究者对该细胞系进行了转染来促进不同强度的EGFR-19del以及EGFR-L858R表达，发现同样可以导致p-EGFR和PD-L1表达水平的升高。③研究者发现吉非替尼可以逆转EGF激活导致的p-EGFR以及PD-L1表达上调；可以逆转Beas-2B-EGFR-L858R细胞系PD-L1表达上调；可以降低PC-9、HCC827细胞系的PD-L1蛋白表达；吉非替尼不会使H1975细胞系p-EGFR以及PD-L1表达发生变化，但C0-1686（三代EGFR-TKI）可以使该细胞系PD-L1表达下调。④研究者进一步研究认为EGFR突变是通过p-ERK 1/2/p-c-jun信号通路而不是p-AKT/p-S6通路影响PD-L1的表达。该研究团队进一步验证了Azuma团队的相关研究，不仅说明了EGFR突变可以导致人NSCLC细胞系PD-L1表达上调，并对EGFR影响PD-L1表达的通路机制进行了简单探索。
随后，Lin等[11]通过流式细胞分析技术发现EGFR突变细胞系（PC-9、HCC827、NCI-H1650）比EGFR野生型细胞系（NCI-H1299、NCI-H460、SPC-A1）PD-L1表达高。同样，为了确定EGFR的激活可以诱导PD-L1表达，研究者应用了重组人EGF（100 ng/mL）刺激H460细胞系，24 h后在该细胞系中发现了升高的PD-L1 mRNA及蛋白质。充分说明EGFR激活可导致PD-L1表达上调。研究者进一步对PC-9以及HCC827细胞系进行不同剂量吉非替尼培养48 h后发现，其PD-L1表达水平下调并且呈剂量依赖型。对严重免疫缺陷小鼠移植PC-9细胞系后应用吉非替尼并与溶媒组进行对比，发现应用吉非替尼的小鼠PD-L1表达低于对照组。相较之前的研究，该研究进一步说明应用EGFR-TKIs可以降低小鼠体内PC-9细胞系的PD-L1表达。
Ota研究团队[12]在2015年通过RT-PCR及流式细胞分析技术对EGFR突变细胞系（HCC827、H1975、PC-9、11-18、H1650）及野生型细胞系（H322、A549、1-87、LK87、H23、H2122、H1437、H1573、H1944、H157、H596、H460、H1299）的PD-L1 mRNA以及PD-L1细胞膜蛋白表达进行检测。发现EGFR突变型细胞系PD-L1 mRNA以及细胞膜蛋白表达均高于野生型。并且进一步发现，应用厄洛替尼可以使HCC827细胞系PD-L1 mRNA以及PD-L1细胞膜蛋白表达下调。
2016年Zhang等[13]同样采用RT-PCR和蛋白印迹分析技术对NSCLC细胞株EGFR野生型（A549、H1299、SPC-A1）和突变型（PC-9、H1975、HCC827）细胞系进行研究，发现EGFR突变细胞系PD-L1表达高于野生型。但H1299与PC-9细胞系PD-L1表达相近，考虑与PC-9细胞系TP53缺失有关，并且已有研究[14]证实其与PD-L1表达水平具有相关性，这也就说明共突变的存在可以进一步影响PD-L1的表达水平。同时该研究团队进一步发现，EGFR突变影响PD-L1表达的通路可能为IL-6/JAK/STAT3。
2019年Guo研究团队[15]对人NSCLC细胞系H522、H661、HCC827、H1299、HCC2935、H1650、H1792、H1975进行蛋白印迹技术检测发现，三种EGFR突变细胞系（HCC827、HCC2935、H1975）PD-L1表达水平高于EGFR野生型细胞系（H522、H661、H1792、H1299）。为了进一步探究EGFR突变对PD-L1表达的影响，研究者对H661细胞系进行转染（e19del、e19del+T790M、L858R、L858R+T790M），发现经转染的细胞系PD-L1表达高于EGFR野生型细胞系。该研究较其他研究进一步发现了EGFR突变细胞系较野生型细胞系IκBα及低氧诱导因子-1α（hypoxia inducible factor-1α, HIF-1α）升高。
在进行EGFR突变对PD-L1表达影响的基础研究过程中，Abdelhamed团队[16]、Lastwika团队[17]的研究结果也显示了EGFR突变可以上调PD-L1表达，并分别对相关影响通路AKT/STAT3以及AKT/mTOM进行了进一步的简要探索。
1.2. 临床研究
见表 2。Azuma团队[9]在体外细胞系研究的基础上进一步对164例NSCLC患者进行PD-L1表达检测发现，EGFR突变患者PD-L1表达率明显高于EGFR野生型（P < 0.001），且EGFR突变是导致PD-L1表达上调的独立因素（OR=25.4, 95%CI: 2.9-47.9, P=0.027）。
2.
已发表NSCLC患者EGFR突变状态与PD-L1表达相关性的研究汇总
Published report that have studied the relationship of EGFR mutation and PD-L1 expression in NSCLC
| Author (Year) |
Ethnicity (Country) |
PD-L1 Ab | Patient number (EGFR mutation) |
Ad/Sq/other | Ⅰ/Ⅱ/Ⅲ/Ⅳ | Method | Cut-off | Influence |
| PD-L1: programmed death ligand 1; EGFR: epidermal growth factor receptor; NSCLC: non-small cell lung carcinoma; Ad: adenocarcinoma; Sq: squamous cell carcinoma. | ||||||||
| Azuma[9] (2014) | Asian (Japan) | Lifespan Bioscience | 164 (57) | 114/50 | 67/46/51/0 | IHC | Intensity×extent | Up |
| D’Incecco[18] (2015) | Caucasian (Italian) | Ab58810 | 125 (56) | 83/23/19 | 0/0/0/125 | IHC | ≥5% | Up |
| Tang[19] (2015) | Asian (China) | E1L3N | 170 (99) | Ad 145 Non-Ad 25 | 0/0/9/161 | IHC | H-score≥5% | Up |
| Song[20] (2016) | Asian (China) | Proteintech | 385 (205) | 385/0/0 | 121/79/185/0 | IHC | ≥5% | Up |
| Huynh[21] (2016) | Caucasian (America) | E1L3N | 261 (54) | 261/0/0 | 201/34/22/4 | IHC | ≥1%；≥5%；≥50% | Down |
| Ji[22] (2016) | Asian (China) | Ab174838 | 100 (60) | 100/0/0 | 42/27/41 | IHC | > 5% 2+ (moderate) | Down |
| Inoue[23] (2016) | Asian (Japan) | E1L3N | 654 (132） | 430/179/45 | 416/113/125 | IHC | H-score≥5 | Down |
| Dong[24] (2017) | Asian (China) | SP142 | 255 (Unclear) | Unclear | Unclear | IHC | < 5%；5%-49%；≥50% | Down |
| Takada[25] (2017) | Asian (Japan) | SP142 | 499 (112) | 417/82/0 | 354/82/63 | IHC | 1%; 5%; 10%; 50% | Down |
| Takada[26] (2018) | Asian (Japan) | SP142 | 441 (223) | 441/0/0 | 339/54/40/8 | IHC | 0%; 1%-4%; 5%-49%; ≥50% | Down |
| Lee[28] (2019) | Asian (Korea) | 22C3 | 1, 000 (424） | 785/188/27 | 621/167/140/30 | IHC | < 1%; 1%-49%; ≥50% | Down |
| Yang[29] (2014) | Asian (Taiwan) | Proteintech | 163 (97) | 163/0/0 | 163/0/0/0 | IHC | ≥5% | No |
| Yang[30] (2016) | Asian (Taiwan) | Proteintech | 105 (17) | 0/105/0 | 105/0/0/0 | IHC | ≥5% | No |
| Zhang[31] (2014) | Asian (China) | SAB 2900365 | 143 (76) | 143/0/0 | Ⅰ: 66; Ⅱ-Ⅲ: 77 | IHC | Quickscore (range 0-18) | No |
| Cooper[32] (2015) | Caucasian (Australian) | 22C3 | 678 (33) | 276/271/131 | 49/271/315 | IHC | ≥50% (any intensity) | No |
| Kim[33] (2015) | Asian (Korean) | E1L3N | 331 (7) | 0/331/0 | 131/118/79 | IHC | ≥10% (any intensity) | No |
| Schmidt[34] (2015) | Caucasian (German) | E1L3N | 321 (6) | 125/149/47 | 187/83/51 | IHC | ≥5% 2+ (moderate) | No |
| Gainor[35] (2016) | Caucasian (America) | E1L3N | 95 (68) | 48/9/1 | Unclear | IHC | ≥1%; ≥5%; ≥50% (any intensity) | No |
| Ameratunga[36](2016) | Caucasian (Australian) | E1L3N | 522 (27) | 288/182/57 | Unclear | IHC | > 5% 2+ (moderate) | No |
D’incecco等[18]对125例晚期NSCLC患者进行PD-L1表达分析，其中包括56例EGFR突变、29例KRAS突变、10例ALK突变、30例EGFR/KRAS/ALK野生型。在进行分析的标本中，有78.4%的标本来自于原发病灶，13.6%的标本来自于转移病灶。其中123例标本成功进行了PD-L1表达评估，中位表达水平为75。对29例三阴性患者标本进行评估后发现中位PD-L1表达水平是20，明显低于EGFR突变120（P < 0.001）、ALK突变115（P=0.02）、KRAS突变55（P=0.06）。在EGFR突变标本中PD-L1阳性率较高，具有统计学差异（P < 0.001）。
Tang等[19]研究了170例晚期NSCLC患者的PD-L1过表达率是65.9%（112/170）。其中，99例患者存在EGFR突变。PD-L1过表达在EGFR突变患者与野生型患者中分别占71.9%（64/89）、57.1%（32/56）（P=0.067）。
Song等[20]对385例肺腺癌PD-L1表达情况进行研究。该研究中，肿瘤比例评分（tumor proportion score, TPS）≥5%视为表达阳性。该研究发现205例EGFR突变患者中，112例（54.6%）PD-L1表达阳性；180例EGFR野生型患者中74例（41.1%）表达阳性（P=0.008）。研究者进一步发现在385例患者中有24例存在基因突变共表达的情况，且共突变比单基因突变对PD-L1阳性表达的影响更大（P < 0.001）。205例EGFR突变患者中包括14例共突变患者，这就说明基因共突变存在也是可能影响研究结果的因素。
2. EGFR突变导致PD-L1表达下调的临床研究
Huynh等[21]对261例肺腺癌进行PD-L1表达评估。该研究排除既往进行过新辅助化疗的患者。包括54例EGFR突变患者，有5例TPS≥5%，49例TPS < 5%。该研究发现，EGFR突变与PD-L1表达呈负相关（P < 0.001）。
Ji等[22]对100例原发性肺腺癌患者标本进行PD-L1表达情况检测。已排除既往行新辅助化疗或有过恶性肿瘤病史的患者。该研究将cut-off值设置为5%。60例EGFR突变患者中，42例PD-L1低表达，18例高表达；EGFR野生型患者中18例低表达，22例高表达。该研究发现存在EGFR突变的患者PD-L1表达降低（P=0.012）。
Inoue等[23]对654例NSCLC患者进行研究，包括腺癌430例（65.7%）、鳞癌179例（27.4%）、其他45例（6.9%）。其中EGFR突变患者132例（20.2%），PD-L1表达阳性25例（12.4%），阴性107例（23.6%）；EGFR野生型522例（79.8%），PD-L1表达阳性176例（87.6%），阴性346例（76.4%）。该研究同样发现EGFR突变可以下调PD-L1表达（P=0.001）。
Dong等[24]对15项研究进行了汇总分析发现存在EGFR突变的患者PD-L1表达较低（OR=1.79, 95%CI: 1.10-2.93, P=0.02）。为了对该汇总分析结果进行验证，研究者对肿瘤基因图谱研究（The Cancer Genome Atlas, TCGA）中的237例肺腺癌患者进行反向蛋白质阵列分析（reverse phase protein microarray, RPPA），发现EGFR突变患者的PD-L1表达蛋白要比EGFR野生型低（P=0.014）；并对通过全基因组测序（whole-genome sequencing, WGS）对广东省肺癌研究所（Guangdong Lung Cancer Institute, GLCI）的mRNA情况进行分析，也显示EGFR突变患者PD-L1表达低于EGFR野生型患者（P=0.044）。研究者进一步对GLCI 255例NSCLC患者分析发现，EGFR突变和PD-L1表达具有负相关性（P=0.014）。
2017年Takada研究团队[25]检测了499例原发NSCLC患者PD-L1表达情况，并采用了4种不同cut-off值进行评估。这些患者中排除新辅助治疗以及既往头颈部、食道鳞癌患者。EGFR突变在腺癌患者中检测，其中有效标本为235例，包括112例（47.7%）突变型以及123例野生型（52.3%）。按照1%、5%、10%、50% cut-off值分别进行分类的情况下，EGFR突变肺腺癌患者的PD-L1表达均低于EGFR野生型患者。于2018年，该研究团队[26]再次对441例原发肺腺癌PD-L1表达情况进行研究发现，EGFR野生型与PD-L1的阳性表达具有相关性（P < 0.000, 1）。同时，该研究进一步发现EGFR不同位点的突变与PD-L1表达无明显相关性（P=0.599, 9），但PD-L1 TPS 5%-49%在EGFR 19del患者中明显高于EGFR外显子21 L858R突变（12.2% vs 2.6%）。
Li等[27]分析了21项研究的4, 857例患者，1, 435例存在EGFR突变的患者中608例（36.7%）存在PD-L1阳性表达；3, 422例突变野生型患者中1, 456例（44.1%）存在PD-L1阳性表达。PD-L1表达与EGFR野生型存在相关性（OR=0.68, 95%CI: 0.48-0.96, P=0.03）。
近期，Lee等[28]对1, 000例手术切除NSCLC患者（腺癌785例，鳞癌188例，21例大细胞神经内分泌癌，4例类癌，2例小细胞肺癌）PD-L1表达情况进行了研究。在按照 < 1%、1%-49%、≥50% cut-off值分别进行分类的情况下，发现肺腺癌中存在EGFR突变患者（424例）的PD-L1表达率明显低于EGFR野生型患者（P < 0.000, 1）。
3. EGFR突变导致PD-L1表达改变无统计学意义
2014年Yang等[29]对163例肺腺癌患者PD-L1表达情况进行研究。PD-L1 TPS≥5%视为表达阳性。结果显示，PD-L1阳性表达率为39.9%（65/163），但其阳性表达水平与常见的肺腺癌突变基因EGFR（P=0.193）、KRAS（P=0.268）、BRAF（P=0.438）和ALK（P=0.564）均没有相关性。2016年该团队又对105例肺鳞癌患者PD-L1表达情况进行研究[30]。同样，PD-L1 TPS≥5%视为表达阳性。PD-L1阳性表达率为56.2%（59/105），且阳性表达水平与突变基因EGFR（P=0.561）、KRAS（P=0.255）、BRAF（P=0.064）和ALK（N/A）均不具有相关性。
Zhang[31]对143例肺腺癌PD-L1表达情况进行分析。并排除既往行新辅助化疗或有过恶性肿瘤病史的患者。76例EGFR突变患者中，37例PD-L1表达阳性，39例表达阴性，差异无统计学意义（P=0.946）。
Cooper研究团队[32]检测了678例NSCLC患者PD-L1表达情况。其中包括腺癌276例、鳞癌271例、大细胞癌116例、混合3例、其他病理类型12例。肿瘤细胞TPS显示≥50%或H-Score≥50考虑为PD-L1高表达。EGFR突变患者两种分级方法中不同PD-L1表达情况患者的数量均相同。EGFR野生型且PD-L1 TPS < 50%的患者222例（93.7%），PD-L1 TPS≥50%的患者15例（6.3%）；EGFR突变型PD-L1 TPS < 50%的患者33例（100%），差异无统计学意义（P=0.23）。
Kim[33]、Schmidt[34]、Gainor[35]、Ameratunga[36]等团队，在相关研究的过程中也发现NSCLC患者PD-L1表达情况与EGFR基因状态无明显相关性。
4. 研究结果不一致原因分析
在对既往相关研究进一步学习的过程中，我们不难发现，EGFR突变对PD-L1表达相关影响的研究结果存在不一致性，我们总结出以下几点可能的原因：①大多数临床研究为回顾性研究，存在选择偏倚，且纳入患者数量不同，有些研究纳入患者数量较少。②在这些研究中，患者基线特征的异质性也会影响研究的结果，比如患者不同地域的分布、病理分型及分期。有相关研究显示，亚裔EGFR突变概率要高于非亚裔，在亚洲人群中EGFR突变在NSCLC中占39.6%，在肺腺癌中更是高达50%[37]；鳞癌与腺癌基因突变的概率与种类不同[38]；PD-L1阳性表达在鳞癌NSCLC中比腺癌更常见[39, 40]。③免疫治疗领域目前缺乏关于PD-L1标准化测试，许多不同的评分标准与试剂被应用[41]。有研究[42]发现对同一标本应用不同抗体PD-L1蛋白表达结果不同；另外有研究发现，应用SP142染色的PD-L1表达阳性率低于其他抗体，如：28-8、22C3和SP263[43]。④PD-L1阳性表达的临界值不同。⑤依据既往研究传统化疗[44]、抗血管治疗[45-47]、EGFR-TKIs[10, 11]均会对PD-L1表达有影响，本文提及的临床研究部分未明确描述进行PD-L1检测前既往治疗情况。
5. 总结与展望
随着PD-1/PD-L1抑制剂治疗NSCLC相关研究的不断进展，肿瘤突变驱动基因对其治疗疗效的影响随之被关注。肿瘤微环境是肿瘤细胞赖以生存和发展的复杂环境，肿瘤细胞PD-L1表达情况与PD-1/PD-L1免疫抑制剂治疗效果存在一定相关性。因此，EGFR通路对PD-L1表达的影响也被进一步探索。虽然目前相关研究结果存在差异，但我们期待在未来研究的过程中可以对EGFR突变影响PD-L1表达水平的多条信号通路进行探索，并完成多中心、随机性、前瞻性的临床研究。希望在进一步的探索过程中，可以为EGFR突变患者找到提高PD-1/PD-L1抑制剂治疗疗效的突破点。
Funding Statement
本文受解放军总医院医疗大数据研发项目（No.2017MBD-013）资助
This paper was supported by the grant from the Medical Big Data Research and Development Project of Chinese PLA General Hospital (to Jinliang WANG)(No.2017MBD-013)
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