以PD-1和PD-L1为靶点的肿瘤免疫治疗研究进展

近年来,肿瘤免疫治疗取得了显著的进展,对肿瘤患者有良好的疗效,成为继手术、放疗和化疗后治疗恶性肿瘤的新模式。目前,程序性死亡受体1(PD-1)/程序性死亡受体配体1(PD-L1)为靶点的免疫治疗是当前肿瘤免疫治疗的研究热点。PD-1是一种抑制T细胞炎性活动的细胞表面受体,属于B7-CD28受体家族成员,常在患者的T细胞中表达;PD-L1是B7家族中的共刺激信号分子,在多种肿瘤细胞和肿瘤组织中均有表达,PD-1/PD-L1通路在诱导效应T细胞凋亡、抑制T细胞活化、抑制机体抗肿瘤免疫反应和肿瘤免疫逃逸过程中发挥重要作用。目前以PD-1和PD-L1为靶点的肿瘤免疫治疗主要分为如下五类:小分子抑制剂、单克隆抗体、双特异性抗体、抗体药物偶联物以及细胞免疫治疗。本研究针对这五类治疗的最新进展进行综述。     

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。     

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。     

分子成像与肿瘤靶向治疗*

肿瘤关键分子靶点的异常表达（表达水平和表达状态）与分子靶向治疗反应、治疗效果及预后密切相关。因此,精准评价肿瘤关键分子表达水平和表达状态,无论在肿瘤分子靶向治疗开展前、过程中以及治疗后均显得尤为关键。分子成像可以无创、实时而全面地对肿瘤关键靶点的表达水平及表达状态进行定性、定量研究,对筛选优势人群、指导治疗、判断预后具有重大意义。本文简述基于不同分子探针的分子成像技术在肿瘤靶向治疗过程中的应用,对比分析分子成像在靶向治疗中的价值,以期有益于新型治疗策略的开发。      

c-Met靶向成像在肿瘤诊断中的应用

肝细胞生长因子受体(c-Met)是一种酪氨酸激酶型受体，对于肿瘤的发生发展至关重要，c-Met靶向治疗已初步应用于临床，其对于癌症患者的治疗具有显著的益处。目前，由于无法对c-Met表达阳性的肿瘤患者进行有效的早期筛选，使得c-Met靶向治疗在肿瘤治疗中总体有效率偏低。c-Met靶向分子成像借助靶向分子成像探针能够实现肿瘤c-Met表达水平及活化状态的定量检测和直观揭示，对于肿瘤的早期诊断、治疗和预后具有重要意义和巨大的潜在价值。结合近年来c-Met靶向分子成像的研究，本文将深入分析、探讨c-Met靶向分子成像探针的构建及其在肿瘤诊断中的应用。     

PD L1信号在肿瘤免疫应答中的作用

PD-L1分子是近年新克隆的B7家族成员,其受体为PD-1,并可能存在另一受体.目前发现,PD-L1分子在肿瘤细胞上表达能影响肿瘤免疫原性,诱导肿瘤特异性CTL凋亡.肿瘤微环境能通过增强树突状细胞PD-L1信号以抑制其功能,干预PD-L1信号为肿瘤免疫治疗开辟了一条新途径.     

TIGIT和PD-1/PD-L1双重阻断途径在肿瘤免疫治疗中的研究进展

程序性死亡蛋白-1和程序性死亡蛋白配体-1(programmed death-1/programmed death-ligand 1,PD-1/PD-L1)作为一种抑制T细胞活化的调节性免疫检查点分子,在肿瘤的免疫治疗发挥着重要的作用。近年来,越来越多的靶向治疗药物得到研发,但是单一免疫检查点阻断剂并不能很好的抑制肿瘤的发生,肿瘤逃逸现象时有发生,而靶向药物的联合治疗可作为抑制肿瘤发生发展的重要手段之一。属于1型脊髓灰质炎病毒受体的抑制性受体T细胞免疫球蛋白和免疫受体酪氨酸抑制基序（immunoreceptor tyrosine-based inhibition motif,ITIM）结构域（T cell immunoglobulin and ITIM domain,TIGIT）是近年靶向药物治疗研究的热点,其与PD-1/PD-L1的联合治疗可减少肿瘤逃逸,更有效地抑制肿瘤的发生。因此,本文就TIGIT和PD-1/PD-L1双重阻断途径在肿瘤免疫治疗中的研究进展进行归纳总结,旨在肿瘤免疫治疗提供一定的理论依据。     

胸腺上皮肿瘤中程序性死亡蛋白1及其配体的临床研究进展

近年来,随着免疫治疗及肿瘤微环境概念的广泛普及,许多肿瘤靶向位点被人们关注并投以大量的实验研究。程序性死亡蛋白1及其配体（PD-1/PD-L1）作为目前最热门的一个免疫靶点通路,其抑制剂已经应用于多种恶性肿瘤的治疗当中。胸腺上皮肿瘤（TETs）是一种较为少见的肿瘤,目前已有证据表明PD-L1在TETs中存在高表达水平并且其与疾病的预后相关,因此本文针对PD-1/PD-L1在TETs中的临床研究进展作一综述。     

PD-1/PD-L1免疫治疗在恶性肿瘤中的研究进展

<正>免疫治疗是肿瘤综合治疗的新热点,其中PD-1/PD-L1免疫治疗在很多恶性肿瘤治疗中发挥着重要作用,引起关注。目前,应用于临床治疗的靶向PD-1/PD-L1药物主要有Nivolumab、Pembromizumab和Atezolizumab等,在恶性肿瘤的治疗中已取得显著效果。     

68Ga-DOTA-PDL1P的设计合成及其在黑色素瘤小鼠模型中的应用研究

背景与目的：以程序性死亡[蛋白]-1(programmed death-1,PD-1)/程序性死亡[蛋白]配体-1(programmed death ligand-1,PD-L1)抑制剂为代表的免疫治疗药物在临床上获得巨大成功，但整体有效率差异很大。现阶段在肿瘤开始治疗前，检测患者PD-1/PD-L1的表达情况是临床用药的重要依据，但目前检测PD-L1表达的方法需要获取患者的标本，而获取标本存在创伤性。因此，迫切需要开发一种无创性活体内特异性检测PD-L1表达的方法。我们设计合成了一种新型靶向PD-L1多肽的正电子发射断层显像(positron emission tomography,PET)显像剂⁶⁸Ga-DOTA-PDL1P，本研究通过对⁶⁸GaDOTA-PDL1P的标记率、放射化学纯度及稳定性进行质量控制评估，并在黑色素瘤小鼠模型中进行应用评价，以期获得有转化前景的⁶⁸Ga-DOTA-PDL1P新型免疫PET探针。方法：利用镓-68 (⁶⁸Ga)标记DOTA-PDL1P，并对其放射性化学纯度和...     

循环肿瘤细胞PD-L1表达在恶性肿瘤中的研究进展

近年来,针对PD-1及PD-L1的研究深入,免疫治疗逐渐兴起,但其在实体肿瘤患者中有效率只有20％左右,如何选择受益人群成为研究者面临的首要问题.最新临床研究表明循环肿瘤细胞(CTC)表面表达的PD-L1能够作为一种潜在的生物标志物,对恶性肿瘤的免疫治疗具有指导作用.本文将对CTC PD-L1在各种实体肿瘤中的表达情况...     

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...     

High expression of PD-L1 mainly occurs in non-small cell lung cancer patients with squamous cell carcinoma or poor differentiation

Background: Lung cancer is one of the most lethal cancers worldwide, but studies have shown that the higher the expression of programmed cell death protein 1 ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC), the more likely it will benefit from anti-PD-L1 immunotherapy. The purpose of our study was to collect and analyze abundant clinical samples in order to provide evidence for clinicians and patients who might consider anti-PD-L1 immunotherapy while jointly formulating treatment plans. Methods: On the one hand, we obtained cases from The Cancer Genome Atlas (TCGA) database, including 498 lung squamous cell cancer (LUSC) patients and 515 lung adenocarcinoma (LUAD) patients. We studied the lung caner driver gene in LUSC and LUAD. On the other hand, PD-L1 expression was detected in lung cancer tissues of 1,008 NSCLC patients with immunohistochemistry staining (IHC), and we studied the correlation between PD-L1 protein expression and clinicopathological characteristics. Results: PD-L1 expression was higher in LUSC than in LUAD at the mRNA level. In univariate analysis, PD-L1 expression at the protein level was higher in patients who were males, were LUSC, were smokers, had a tumor diameter >3 cm, had poor differentiation, or had stages III~IV disease. In multivariate analysis, PD-L1 expression was higher in patients who were LUSC or in poor differentiation. Conclusion: In term of protein level, PD-L1 expression was higher in NSCLC patients who were LUSC or in poor differentiation. We recommend that PD-L1 IHC detection can be routinely performed in such populations that are likely to benefit most from PD-L1 immunotherapy.     

Biomarkers for immune checkpoint inhibition in non–small cell lung cancer (NSCLC)

The emergence of immunotherapy has dramatically changed how non–small cell lung cancer is treated, and longer survival is now possible for some patients, even those with advanced disease. Although some patients achieve durable responses to checkpoint blockade, not all experience such benefits, and some suffer from significant immunotoxicities. Given this, biomarkers that predict response to therapy are essential, and testing for tumor programmed death ligand 1(PD-L1) expression is the current standard. The extent of PD-L1 expression determined by immunohistochemistry (IHC) has demonstrated a correlation with treatment response, although limitations with this marker exist. Recently, tumor mutational burden has emerged as an alternative biomarker, and studies have demonstrated its utility, irrespective of the PD-L1 level of a tumor. Gene expression signatures, tumor genotype (such as the presence of an oncogenic driver mutation), as well as the density of tumor-infiltrating lymphocytes in the tumor microenvironment also seem to affect response to immunotherapy and are being researched. Peripheral serum markers are being studied, and some have demonstrated predictive ability, although most are still investigational and need prospective validation. In the current article, the authors review the biomarker PD-L1 as well as other emerging and investigational tissue-based and serum-based markers that have potential to better predict responders to immunotherapy.     

肿瘤免疫治疗PD-1/PD-L1靶向核素分子探针的研究进展

Bone and soft tissue tumor is a rare disease and its incidence is low. There are few studies on this kind of tumors in the world every year. Based on the research of bone and soft tissue tumor in recent years, this paper reviews the core contents of osteosarcoma, Ewing’s sarcoma, soft tissue sarcoma, sarcomas followup, targeted therapy and immunotherapy. At the same time, we analyze the unsolved problems and put forward the solutions and suggestions to provide references for clinicians in this field. © 2020, CHINA RESEARCH ON PREVENTION AND TREATMENT. All rights reserved.     

The Significance of the PD-L1 Expression in Non–Small-Cell Lung Cancer: Trenchant Double Swords as Predictive and Prognostic Markers

Lung cancer is the leading cause of death due to cancer worldwide. Surgery, chemotherapy, and radiotherapy have been the standard treatment for lung cancer, and targeted molecular therapy has greatly improved the clinical course of patients with non–small-cell lung cancer (NSCLC) harboring driver mutations, such as in epidermal growth factor receptor and anaplastic lymphoma kinase genes. Despite advances in such therapies, the prognosis of patients with NSCLC without driver oncogene mutations remains poor. Immunotherapy targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) has recently been shown to improve the survival in advanced NSCLC. The PD-L1 expression on the surface of tumor cells has emerged as a potential biomarker for predicting responses to immunotherapy and prognosis after surgery in NSCLC. However, the utility of PD-L1 expression as a predictive and prognostic biomarker remains controversial because of the existence of various PD-L1 antibodies, scoring systems, and positivity cutoffs. In this review, we summarize the data from representative clinical trials of PD-1/PD-L1 immune checkpoint inhibitors in NSCLC and previous reports on the association between PD-L1 expression and clinical outcomes in patients with NSCLC. Furthermore, we discuss the future perspectives of immunotherapy and immune checkpoint factors.     

Impact of copy number variant and single nucleotide polymorphism of the programmed death-ligand 1 gene,programmed death-ligand 1 protein expression and therapy regimens on overall survival in a large group of Caucasian patients with non-small cell lung carcinoma

Anti-programmed death-1 or anti-programmed death-ligand 1 (PD-L1) blockade may be ineffective in some patients with non-small cell lung cancer (NSCLC) with high percentage of tumor cells with PD-L1 expression. In addition, immunotherapy may provide great benefits in patients without PD-L1 expression. The present study assessed PD-L1 protein expression by immunohistochemistry, copy number variation (CNV) of PD-L1 and two single nucleotide polymorphisms (SNPs), rs822335 and rs822336, in the promoter of PD-L1 by quantitative PCR in 673 patients with NSCLC. Overall survival time of patients with NSCLC depending on the assessed predictive factors (PD-L1 CNV or SNP) and the treatment methods (immunotherapy in first/second line of treatment or chemotherapy) was analyzed. The present study revealed significantly higher PD-L1 copies number in patients with ≥10% and ≥50% of tumor cells with PD-L1 expression compared to patients with lower percentage of PD-L1-positive tumor cells (P=0.02 and P=0.0002, respectively). There was a significant positive correlation (R=0.2; P=0.01) between number of PD-L1 copies and percentage of tumor cells with PD-L1 protein expression. Percentage of tumor cells with PD-L1 expression was lower in patients with TT genotype of the rs822335 polymorphism compared to those with CC genotype (P=0.03). The present study observed significantly higher risk of death in patients treated with chemotherapy compared to those treated with immunotherapy (P<0.0001; hazard ratio=2.4768; 95% confidence interval, 2.0120–3.0490). The present study demonstrated a close relationship between PD-L1 copies number, genotype of rs822335 PD-L1 polymorphism and PD-L1 protein expression on tumor cells. However, the impact of CNV and SNPs of PD-L1 on overall survival of patients with NSCLC requires further investigation.