PD-1/PD-L 1抗体在非小细胞肺癌治疗中的研究现状

程序性死亡因子1(programmed death-1,PD-1)存在于活化的T细胞和 B细胞表面,是一种重要的免疫共抑制分子。当 PD-1与程序性死亡配体1/2(programmed death-ligand 1/2, PD-L1/2)结合后,可以引起一系列的免疫抑制作用,并使肿瘤逃避免疫破坏。阻断 PD-1/PD-L1通路,则可能减弱其对免疫活性细胞的抑制作用,从而达到增强细胞免疫、杀灭肿瘤细胞的目的。目前大量研究证明PD-1/PD-L1抗体在非小细胞肺癌治疗中有显著的抗肿瘤活性。本文将对其研究现状加以综述。     

Natural course of chronic hepatitis B is characterized by changing patterns of programmed death type-1 of CD8-positive T cells

AIM:To investigate if and how programmed death type-1(PD-1)expression affects the natural course of hepatitis B virus(HBV)infection. METHODS:Sixty-four patients in different natural stages of chronic HBV infection were enrolled in this study.PD-1 expression in total T cells was detected by flow cytometry.Levels of total CD8+T cell responses and proliferation in relation to PD-1 expression levels were analyzed with intracellular staining and PD-1/ PD-L1 blockage. RESULTS:The PD-1 expression in T cells was dy...     

PD-1/PD-L1通路在非小细胞肺癌中的研究进展

程序性死亡受体-1(PD-1)/程序性死亡配体-1(PD-L1)信号途径参与肿瘤的免疫逃逸。PD-L1蛋白在非小细胞肺癌组织中存在不同程度的表达,其表达程度与肿瘤细胞的分化程度、临床分期、淋巴转移及预后等相关联。PD-L1可能通过保持非小细胞肺癌肿瘤浸润性树突状细胞的不成熟状态,增强调节性 T 细胞功能,与浸润性淋巴细胞表面高表达的 PD-1相互作用诱导 CD8+ T 细胞凋亡等机制介导肺癌的免疫豁免。目前针对 PD-1/PD-L1途径的临床免疫治疗试验已经在非小细胞肺癌中取得一定的疗效,成为非小细胞肺癌免疫治疗的新靶向。     

PD-1/PD-L1信号通路与慢性乙型肝炎

目的：程序性死亡分子-1（programmed death-1,PD-1）是近年来发现的属于B7/CD28家族的重要协同刺激分子,与其配体（programmed death -1 ligand,PD-L）结合后在调节T淋巴细胞的活化、分化及增殖功能方面起着重要作用。在慢性HBV感染不同阶段,PD-1表达水平存在差异,且与肝脏炎症程度、ALT及病毒载量等密切相关。通过不同途径阻断PD-1/PD-L1通路可以使耗竭的T淋巴细胞功能得到改善,提示可能是未来抗病毒治疗的方向之一。     

PD-1/PD-L通路对乙型肝炎病毒感染结局的影响

程序性死亡因子-1(programmed death 1,PD-1)是可以表达在T淋巴细胞膜表面的负向协同刺激分子受体,他与PD-1配体(programmeddeath 1 ligand,PD-L)形成通路后,可以减弱T淋巴细胞免疫反应,甚至导致T淋巴细胞功能衰竭.近来研究表明PD-I/PD-L通路的形成可以影响HBV...     

PD-1/PD-L1信号通路在乙型病毒性肝炎免疫调节作用的研究进展

程序性死亡分子1(programmed death-1,PD-1)是由pdcdl基因编码的一个抑制性共刺激分子,在维持外周耐受中起着关键性的作用,并在慢性病毒感染、肿瘤免疫及自身免疫性疫病的发生过程中发挥重要的生物学作用,受到广泛的关注.本文主要综述PD-1/PD-L1信号通路在乙型病毒性肝炎免疫调节作用的研究进展.     

阻断肝癌细胞PD-L1对共培养的树突状细胞成熟的影响

目的:探讨通过阻断肝癌细胞的程序性死亡配体1(PD-L1)对共培养的树突状细胞成熟的影响。方法:健康人外周血分离出单个核细胞(PBMC),加入IL-4、GM-CSF诱导成未成熟树状突细胞，再加入TNF-α诱导成成熟树突状细胞；对照组为肝癌细胞系HepG2与未成熟树突状细胞共培养，实验组为经PD-L1抗体处理的肝癌细胞系HepG2与未成熟树突状细胞共培养，比较两组树突状细胞HLA-DR、CD80和CD83的表达。结果:肝癌细胞HepG2细胞系中，PD-L1阳性表达率为(25.81±0.86)%;HLA-DR、CD80和CD83在成熟树突状细胞中阳性率分别为(83.20±1.25)%、(26.55±0.84)%和(7.99±0.16)%,对照组中树突状细胞群分别降至(64.74±1.02)%、(8.84±0.56)%和(2.07±0.10)%,两组比较差异有统计学意义(P<0.05);实验组中分别降至(76.21±0.96)%、(22.02±0.88)%和(3.36±0.15)%,与对照组比较差异有统计学意义(P<0.05)。结论:通过阻断肝癌细胞的PD-L1,可以减弱对共培养...     

PD-1/PD-L1抑制剂在晚期结直肠癌中应用的研究进展

结直肠癌是世界范围内常见的恶性肿瘤,近年来其发病率不断上升,发病人群日趋年轻化.目前,手术切除仍然是结直肠癌的首选治疗方法.但结直肠癌早期症状隐匿,大多数患者在就诊时已处于晚期,错过了最佳手术时机.而针对晚期结直肠癌(mCRC)的治疗方式主要有放疗、化疗、分子靶向治疗等,但往往随着治疗日久而出现大量并发症或耐药现象.免...     

The clinicopathological and prognostic significance of PD-L1 expression in pancreatic cancer: A meta-analysis

Background: Immunotherapy has shown promise against solid tumors. However, the clinical significance of programmed cell death 1(PD-1) and programmed cell death ligand 1(PD-L1) in pancreatic ductal adenocarcinoma(PDAC) remains unclear. This meta-analysis aimed to analyze the prognostic effect of PD-L1 in PDAC.Data sources: Electronic search of the Pub Med, Cochrane Library and Web of Science was performed until December 2016. Through database searches, we identified articles describing the relationship between PD-L1 status and PDAC patient prognosis. Meta-analysis was performed to investigate the relationship between PD-1 and overall survival(OS).Results: Nine studies with 989 PDAC patients were included for PD-L1 expression analysis. And 5 studies with 688 PDAC patients were included in the prognostic analysis. The PD-L1 positive rate measured by immunohistochemistry(IHC) was higher than that measured by polymerase chain reaction(PCR)(P 0.001). PDAC patients with high expression levels of PD-L1 had significantly reduced OS(HR = 2.34;95% CI: 1.78–3.08). Subgroup analysis showed that the prognostic effect of PD-L1 levels was similar between the IHC and PCR methods. The PD-L1 positive rate was associated with PDAC T stages; the PD-L1 positive rate in the T3–4 group was higher than that in the T1-2 group(OR = 0.37; P = 0.001).Conclusions: High PD-L1 expression levels predicted a poor prognosis in PDAC patients. Thus, PD-L1 status helps determine treatment in PDAC patients.     

Advances in immuno-oncology biomarkers for gastroesophageal cancer: programmed death ligand 1, microsatellite instability,and beyond

Blockade of the programmed death ligand 1(PD-L1) and programmed cell death 1(PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction(GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability(MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatmentrefractory solid tumors with MSI status and the thirdline or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.     

IL-17A/F enable cholangiocytes to restrict T cell-driven experimental cholangitis by upregulating PD-L1 expression

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成人社区获得性肺炎患者血清可溶性程序性死亡受体配体-1的表达及意义

通过检测成人社区获得性肺炎(CAP)患者血清可溶性程序性死亡受体配体-1(PD-L1)水平,探讨其临床意义。共纳入44例CAP患者、54例重症CAP患者和30例健康对照者,检测所有研究对象血清中可溶性PD-L1水平,单因素和多因素回归分析各临床参数对预后的影响。结果显示,重症CAP者血清可溶性PD-L1水平为98.20(57.94,128.90)ng/L,高于CAP者[59.32(33.55,92.58)ng/L]和健康对照者[20.44(12.15,36.20)ng/L](P值均<0.001)。可溶性PD-L与CURB-65评分(r=0.481,P<0.001)、肺炎严重指数(PSI)评分(r=0.442,P<0.001)呈显著正相关。单因素回归分析显示,CURB-65评分(HR=2.544,95%CI 1.324~4.889,P=0.005)、PSI评分(HR=1.036,95%CI 1.012~1.061,P=0.004)、可溶性PD-L1水平(HR=1.013,95%CI 1.001~1.026,P=0.041)是CAP患者住院期间死亡的危险因素。多因素回归分析显示,PSI评分(HR=1.042,95%CI 1.012-1.073,P=0.005)、可溶性PD-L1水平(HR=1.011,95%CI 1.002~1.071,P=0.020)是影响CAP患者死亡的独立危险因素。可溶性PD-L1≥98.20 ng/L的CAP患者住院期间生存率显著低于可溶性PD-L1<98.20 ng/L者(P=0.033)。提示成人CAP患者血清可溶性PD-L1水平升高与预后相关,可能是影响患者预后的独立危险因素之一。     

Expression pattern of PD-1/PD-L1 in primary liver cancer with clinical correlation

Immunotherapy, including ICIs, has emerged as an invaluable treatment option for advanced PLC. Nevertheless, the expression patterns of PD-L1 and PD-1 in PLC remain incompletely understood. In this study, the expression pattern and clinical correlation of PD-L1 and PD-1 were analysed in 5245 PLC patients. The positivity rates of PD-L1 and PD-1 were very low in the patient PLCs, but the positivity rates of PD-L1 and PD-1 were higher in the ICC and cHCC-ICC than in HCC. The expression of PD-L1 and PD-1 correlated with the malignant phenotypes and clinicopathological characteristics of PLC. Interestingly, PD-1 positivity might serve as an independent prognostic factor. Based on a systematic analysis of a large amount of PLC tissues, we proposed a novel classification of PD-1/PD-L1 expression in HCC and ICC. In light of this stratification, we observed a close correlation between PD-L1 levels and PD-1 expression in HCC and ICC.     

Comparison of PD-L1 immunohistochemical assays and the significance of PD-L1 expression in thymoma

Thymoma is a relatively rare malignancy, which is categorized as thymic epithelial tumor but known as the most common pathology that is developed in the anterior mediastinum. Complete resection is recommended for localized tumors and usually favorable prognosis can be obtained. However, poor survival period has been reported in unresectable cases exhibiting extensive invasion or distant metastasis, as effective chemotherapeutic regimens are restrained. We previously assessed expression of programmed death ligand 1 (PD-L1) and programmed death 1 (PD-1) and discussed their prospective application in the immunotherapy of thymic epithelial tumors. After our publication, additional studies using reliable PD-L1 antibodies, which are currently administered to predict efficacy of PD-1/PD-L1 blockade therapy were performed and further characterized PD-L1 in thymoma. Herein, recent knowledge in relation to the significance of PD-L1 expression in thymoma is reviewed based on recent findings using qualified PD-L1 clones. Most studies coherently found high expression of PD-L1 on the cell membrane and cytoplasm of tumor epithelial cells in accordance with previous reports, which is a predictive marker for effectiveness of anti-PD-1/PD-L1 drugs, even when approved PD-L1 antibodies were employed. On the other hand, PD-L1 expression on tumor infiltrating immune cells remains to be sufficiently determined. High PD-L1 expression can be expected in cases with high grade histological subtypes, such as type B2/B3 thymomas, or those with advanced stages III or IV of the disease. Interestingly, the level of PD-L1 expression was found to be upregulated after chemotherapy compared with that before, which could be explained by immunogenic cell death. The prognostic impact of PD-L1 expression in thymoma might be found only when thymic carcinoma patients were excluded. Furthermore, it also could be identified when we analyzed thymomas completely resected, distinct from biopsy and incompletely resected cases.