原发性肝细胞肝癌PD-L1蛋白表达及在免疫治疗中的意义

目的探讨程序性死亡配体PD-L1蛋白在原发性肝细胞癌(HCC)中的表达、病理特征及其在免疫治疗中的意义。方法采用免疫组织化学方法,对95例原发性肝细胞肝癌进行PD-L1(22C3)标记,观察肿瘤细胞的PD-L1蛋白表达情况、观察分析其病理特征。结果HCC的肿瘤细胞PD-L1检测PD-L1蛋白表达:cutoff值,TPS≥1%表达为阳性,有7例,其中T≥50%,为强阳性有2例;cutoff值,T<1%或无肿瘤细胞表达,为阴性,有86例。结论PD-L1蛋白在HCC中有一定意义数量的表达,与肿瘤分化程度无明显相关性。免疫治疗近年在HCC肿瘤研究受到了较多的关注,其中靶向PD1/PD-L1抗癌免疫疗法的一些研究结果给晚期HCC患者带来新的希望。PD-L1的检测,将可能为更多HCC患者免疫治疗带来益处,具有一定的临床意义。     

PD-L1表达调控研究进展

摘 要：PD-1/PD-L1信号通路是肿瘤免疫逃逸主要机制之一。通过单克隆抗体与配体或受体结合阻断PD-1和PD-L1之间的相互作用在如黑色素瘤、非小细胞肺癌等多种肿瘤患者中疗效显著,但是只对部分患者有效。已开展的临床研究发现患者肿瘤部位的PD-L1表达量可能与PD-1/PD-L1抑制剂的疗效及预后相关。因此,深入研究PD-L1的表达调控机制有利于为肿瘤免疫治疗提供新的思路和潜在靶点,改进PD-1/PD-L1抑制剂的疗效。全文将PD-L1表达调控分为转录水平和转录后水平,对近几年PD-L1表达调控研究进展作一综述。     

免疫检查点PD-1/PD-L1阻断剂耐药机制的研究进展

免疫检查点蛋白通过复杂机制抑制抗肿瘤免疫,进而介导恶性肿瘤的“免疫逃逸”。2018年诺贝尔生理学或医学奖的两位得主发现了抑制上述机制的癌症疗法,为人类抗肿瘤治疗带来曙光。近年来,针对程序性死亡受体-1（PD-1）/程序性死亡受体配体-1（PD-L1）的免疫检查点阻断治疗在多种恶性肿瘤中取得较好疗效,将肿瘤免疫治疗推向新的里程碑。然而继之出现的耐药问题,限制了其临床应用,成为这一领域新的难题。本文就PD-1/PD-L1阻断剂耐药现象及相关机制作一综述。     

原发性肝癌的发病机制和BUB1表达的临床意义

目的采用生物信息学分析方法探讨原发性肝癌的发病机制,并分析BUB1表达与原发性肝癌临床病理特征和预后的关系。方法通过对比研究癌症基因组图谱(TCGA)数据库中原发性肝癌的mRNA原始表达数据,筛选差异表达基因,采用基因本体(GO)分析、京都基因与基因组百科全书(KEGG)通路分析和蛋白互作用(PPI)网络分析初步探索原发性肝癌的发病机制。分析BUB1mRNA与原发性肝癌临床病理特征和总生存期(OS)的关系。生存分析采用Kaplan-Meier法,多因素分析用Cox比例风险模型。结果原发性肝癌发病机制研究显示,GO条目包括4个生物途径,3个细胞定位,1个分子功能。KEGG通路3条,包括卵母细胞减数分裂、孕酮介导的卵母细胞成熟和细胞周期。PPI网络分析结果显示,处于网络中心节点的蛋白包括CDC20、BUB1、CCNB1和CCNB2等。BUB1mRNA表达水平与原发性肝癌的临床分期和T分期有关(P<0.05),与性别、年龄、淋巴结转移和远处转移无关(P>0.05)。OS与原发性肝癌的临床分期、淋巴结转移、远处转移、T分期和BUB1mRNA表达有关(P<0.05),与性别和年龄无关(P>0.05)。Cox多因素分析显示,BUB1mRNA表达、临床分期和T分期是影响男性原发性肝癌患者OS的独立因素(P<0.05),而远处转移是影响女性原发性肝癌患者OS的独立因素(P<0.05)。亚组分析显示,男性、≥51岁、Ⅰ~Ⅱ期、无淋巴结转移、无远处转移和T1~T2期患者中,BUB1mRNA高表达者的中位OS显著低于BUB1mRNA低表达者(P<0.05)。结论BUB1可能通过参与卵母细胞减数分裂和细胞周期参与原发性肝癌的发生与发展。BUB1mRNA表达影响原发性肝癌的预后。     

PD-L1/PD-1在卵巢癌中的表达机制及免疫治疗研究进展

卵巢癌在妇科肿瘤中致死率最高,放化疗及手术等治疗方法疗效有限,更有效的新型治疗方法亟待开发。近年来免疫疗法成为备受关注的一种新的肿瘤治疗措施,其中抗PD-1/PD-L1疗法在包括恶性黑色素瘤在内的多种肿瘤治疗中取得显著疗效,但其在卵巢癌的临床治疗中效果尚不明确。本文就PD-1/PD-L1信号通路的作用机制和其在卵巢癌预后中的意义作一概述,探讨免疫疗法和其他传统疗法相结合应用于卵巢癌临床治疗中的可行性。     

PD-1/PD-L1抑制剂在晚期肝细胞肝癌治疗中的研究进展

晚期原发性肝细胞肝癌(hepatocellular carcinoma,HCC)的系统治疗主要包括靶向治疗、化疗以及免疫治疗。近3年,程序性死亡受体-1(programmed death receptor-1,PD-1)/程序性死亡受体-1配体(programmed death receptor-1 ligand,PD-L1)抑制剂在晚期HCC治疗中取得突破性进展。纳武单抗(nivolumab)和帕博利珠单抗(pembrolizumab)先后被美国食品药品管理局(FDA)批准用于HCC二线治疗。多个PD-1/PD-L1抑制剂联合系统治疗的Ⅰ、Ⅱ期临床研究初步显示出较好的疗效和安全性。阿特珠单抗(atezolizumab)联合贝伐单抗一线治疗成为首个在Ⅲ期临床研究中证实优于现有标准治疗索拉非尼的全新疗法。本文就近年PD-1/PD-L1抑制剂在晚期HCC治疗中的研究进展进行概述。     

PD-1/PD-L1与IDO抑制剂在原发性肝细胞肝癌免疫治疗中的研究进展

原发性肝细胞癌(HCC)目前的治疗手段多样,除了根治性手术切除外,还包括新型多靶点抗肿瘤药物Sorafinib、联合化疗(如XELOX、FOLFOX4)、经动脉化疗栓塞术、射频消融、无水酒精注射等,但各种治疗手段都有其局限性,疗效不甚满意.随着对HCC病理机制的深入研究和分子生物学技术的发展,免疫检查点抑制剂已成为近年来的热门研究领域,其中,PD-1/PD-L1通路阻断剂和IDO抑制剂作为免疫检查点的代表,已成为争相研究的焦点.二者通过不同机制来阻断肿瘤细胞的免疫逃逸,最终杀灭肿瘤细胞,具有抗多种类型肿瘤的潜力,有望实质性延长患者总生存期.本文结合国内外近期相关研究和临床试验报道,对PD-1/PD-L1和IDO抑制剂在HCC治疗中的研究进展作一简要综述.     

基于PD-1/PD-L1靶点的肿瘤免疫治疗研究进展

近年来的研究显示,肿瘤免疫治疗在恶性肿瘤的治疗上成效显著,疗效优于传统的化疗和放疗.程序性死亡受体-1(programmed death 1,PD-1)和程序性死亡受体配体-1(programmed death-ligand 1,PD-L1)这对免疫共抑制分子作为肿瘤免疫治疗的靶点备受关注,PD-L1在一些肿瘤细胞中的...     

PD-1/PD-L1在三阴乳腺癌中的研究进展

三阴乳腺癌特指雌激素受体、孕激素受体及人表皮生长因子受体2均阴性的乳腺癌患者,由于其对内分泌治疗无效,使其临床预后极差,因此,探索新的治疗方法尤为重要.近年来,肿瘤的免疫治疗已成为继放疗、化疗和手术治疗之后的第4种有效的治疗方法.研究表明,大约20%的三阴乳腺癌表达PD-L1,在介导肿瘤细胞免疫逃逸中起重要作用.本文就PD-1及其配体PD-L1在三阴乳腺癌中的表达、表达机制及其运用作一综述.     

Effect of Primary Systemic Therapy on PD-1, PD-L1, and PD-L2 mRNA Expression in Advanced Breast Cancer

Objective: The association between PD-1, PD-L1, and PD-L2 expression and prognosis has been extensively studied in various cancers but remained controversial in breast cancer. Besides, little is known about the prognostic value of PD-1, PD-L1, and PD-L2 upregulation or downregulation following systemic therapy (chemotherapy and hormonal therapy) in breast cancer. Therefore, we aim to investigate the change of PD-1, PD-L1, and PD-L2 expression in mRNA level after primary systemic therapy in breast cancer patients and its clinical implications. Methods: Expression of PD-1, PD-L1, and PD-L2 mRNA were measured before-after chemotherapy and hormonal therapy with real-time PCR in 80 advanced breast cancer patients. The correlation between alteration of PD-1, PD-L1, and PD-L2 expression and clinicopathological characteristics as well as overall survival was also statistically analyzed. Results: Chemotherapy and hormonal therapy altered PD-1, PD-L1, and PD-L2 expression in breast cancer with most patients have an increase expression. As much as 57.1%, 62.9% and 60% patients have an increase PD-1, PD-L1, and PD-L2 expression after chemotherapy, while 60%, 60%, and 64% patients have an increase PD-1, PD-L1, and PD-L2 expression after hormonal therapy. Alteration of PD-1, PD-L1, and PD-L2 expression was not correlated with all clinicopathological characteristics. Increase in PD-1, PD-L1, and PD-L2 expression was significantly associated with better OS (p=0.031, p=0.019, and p=0.019 for PD-1, PD-L1, and PD-L2, respectively), which remained significant in multivariate analysis including age, stage, primary systemic therapy, histology grade, subtype and primary tumor histology (HR PD-1 0.5 (95% CI 0.28-0.88) p=0.031; HR PD-L1 0.43 (95% CI 0.24-0.8) p=0.019; HR PD-L2 (95% CI 0.24-0.87) p=0.019).  Conclusion: Expression of PD-1, PD-L1, and PD-L2 in breast cancer patients is mostly enhanced after chemotherapy and hormonal therapy, and the enhancement is associated with good OS. This result revealed the potential of measuring PD-1, PD-L1, and PD-L2 mRNA expression in predicting clinical outcome.     

EBUS-TBNA as a Promising Method for the Evaluation of Tumor PD-L1 Expression in Lung Cancer

Background

Because most lung cancers are diagnosed at advanced stages, we are forced to conduct molecular testing using small biopsy samples. Endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) is emerging as a minimally invasive biopsy technique. Here, we examined the usefulness of EBUS-TBNA to evaluate programmed death-ligand 1 (PD-L1) expression in lung cancer.

PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project

IntroductionThe Blueprint Programmed Death Ligand 1 (PD-L1) Immunohistochemistry (IHC) Assay Comparison Project is an industrial-academic collaborative partnership to provide information on the analytical and clinical comparability of four PD-L1 IHC assays used in clinical trials.MethodsA total of 39 NSCLC tumors were stained with four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263), as used in the clinical trials. Three experts in interpreting their respective assays independently evaluated the percentages of tumor and immune cells staining positive at any intensity. Clinical diagnostic performance was assessed through comparisons of patient classification above and below a selected expression cutoff and by agreement using various combinations of assays and cutoffs.ResultsAnalytical comparison demonstrated that the percentage of PD-L1–stained tumor cells was comparable when the 22C3, 28-8, and SP263 assays were used, whereas the SP142 assay exhibited fewer stained tumor cells overall. The variability of immune cell staining across the four assays appears to be higher than for tumor cell staining. Of the 38 cases, 19 (50.0%) were classified above and five (13%) were classified below the selected cutoffs of all assays. For 14 of the 38 cases (37%), a different PD-L1 classification would be made depending on which assay/scoring system was used.ConclusionsThe Blueprint PD-L1 IHC Assay Comparison Project revealed that three of the four assays were closely aligned on tumor cell staining whereas the fourth showed consistently fewer tumor cells stained. All of the assays demonstrated immune cell staining, but with greater variability than with tumor cell staining. By comparing assays and cutoffs, the study indicated that despite similar analytical performance of PD-L1 expression for three assays, interchanging assays and cutoffs would lead to “misclassification” of PD-L1 status for some patients. More data are required to inform on the use of alternative staining assays upon which to read different specific therapy-related PD-L1 cutoffs.     

PD-L1在结直肠癌原发灶中的表达及对肝转移微波消融术后复发的预测价值

目的探讨程序性死亡配体1(PD-L1)在结直肠癌(CRC)肝转移患者原发灶肿瘤细胞(TC)和肿瘤浸润免疫细胞(TIC)中的表达情况,及其对肝转移微波消融(MWA)术后复发的预测价值。方法回顾性收集28例CRC肝转移患者原发灶的石蜡包埋标本,采用免疫组织化学法检测其中PD-L1表达水平,分析其与临床特征的关系。Kaplan-Meier法和Log rank检验进行无复发生存(RFS)分析,Cox比例风险回归模型进行影响复发的多因素分析。结果PD-L1在CRC原发灶TC和TIC中的阳性率分别为14.3%(4/28)和46.4%(13/28)。CRC肝转移患者原发灶TIC的PD-L1表达与肝转移瘤最大径有显著关联(P<0.05),与肝转移MWA术后更差的RFS相关(P<0.05)。CRC肝转移患者原发灶TIC的PD-L1表达、肝转移瘤最大径>3 cm是影响肝转移MWA术后复发的危险因素(P<0.05)。结论CRC肝转移患者原发灶TIC的PD-L1表达可能会增加肝转移MWA术后复发的风险。     

Increased CD8 Tumor Infiltrating Lymphocytes in Colorectal Cancer Microenvironment Supports an Adaptive Immune Resistance Mechanism of PD-L1 Expression

Background: Tumor cells express programmed death ligand-1 (PD-L1) through several biological processes, thereby having different clinical significance depending on the underlying mechanism of expression. Currently, mechanisms leading to PDL1 gene expression in colorectal cancer (CRC) are not fully understood. Methods: We investigated 98 Indonesia CRC patients to determine PD-L1 protein expressions and their correlations with PD-L1 gene copy number status, tumor infiltrating lymphocytes (TILs), tumor mutational profile, as well as clinicopathologic features. Results: Our investigation demonstrated that 18% of patients positively expressed PD-L1. Further analysis on PD-L1 copy number revealed that all PD-L1+ tumors had normal copy number, indicating that the expression of PD-L1 was not a consequence of genetic amplification of PD-L1. From TILs analysis, there was a significant increase of CD8 in all tumor cells expressing PD-L1 (P=0.0051), indicating that the inducible PD-L1 expression was the prominent mechanism occurred in CRC. Furthermore, the expression of PD-L1 in this CRC population was significantly associated with high frequency of MSI compared to the remainder PD-L1- tumors (P=0.0001), suggesting the natural immunogenicity of tumors via MSI status plays role in attracting immune response. On the other hand, p53 mutations which were frequently observed within Indonesian CRCs (76.5%), they were not associated with PD-L1 expression (p=0.1108), as well as KRAS gene (29.6%; p=0.5772) and BRAF gene mutations (5%; p=0.2171). Conclusion: Our study demonstrated that PD-L1 expressions in CRC were predominantly found as a consequence of infiltrating CD8 T lymphocytes that in part arise in the setting of microsatellite instability. Taken together, our findings further support the role of adaptive immune resistance to drive PD-L1 induction in tumor microenvironment and may provide important rationale for strategy implementation of immunotherapy for CRC cases.     

结直肠癌肝转移灶中PD-L1基因阳性患者肝切除后的预后相关因素

目的 探讨直肠癌肝转移灶中PD-L1基因阳性患者肝切除术后预后的相关因素.方法 回顾性分析68例以手术为主的个体化综合治疗结直肠癌肝转移灶中PD-L1基因阳性患者的临床资料,观察手术治疗后疗效及预后,分析相关因素.结果 单因素分析结果显示:无放疗、N分期、RAS基因突变状态、T分期、MMR表达缺失(dMMR)和Duck...     

复发性肝癌再次肝切除的效果

在392例次肝癌切除中,19例为复发性肝癌作再次肝切除.第1次至第2次肝切除的间隔时间平均为35月.作第2次肝切除的肿瘤平均5cm.切除术的类型有剔出术4例,1肝段切除8例,2肝段切除7例.复发性肝癌再次术后生存5年以上4例,最长14年健在.已知死亡6例,其生存平均11个月,表明再次肝切除可提高复发性肝癌的生存期.     

Comparison of Four PD-L1 Immunohistochemical Assays in Lung Cancer

Introduction

Four different programmed death ligand 1 immunohistochemical assays are approved or in development as companion or complementary diagnostics to different immunotherapeutic agents in lung carcinoma. We sought to determine whether these assays are technically equivalent and whether one antibody can be used on an alternate staining platform.