外泌体PD-L1在肿瘤免疫治疗中的研究进展

近年来,肿瘤免疫治疗取得了重大的进步,目前以程序性细胞死亡蛋白1(programmed cell death protein-1,PD-1)/程序性细胞死亡蛋白-配体1(programmed cell death protein-ligand 1,PD-L1)抑制剂为代表的新型免疫治疗临床应用如火如荼进行中,但在PD-1/PD-L1抑制剂应用中,不同患者和不同肿瘤类型之间疗效差异显著。现有研究发现外泌体PD-L1能解释这种疗效差异,主要机制是外泌体PD-L1可代替细胞PD-L1,产生抑制T细胞活化作用,同时,还可将功能性PD-L1转移到其他细胞,产生免疫抵抗或免疫耐受,影响PD-1/PD-L1抑制剂治疗结局。本文将对外泌体PD-L1与肿瘤免疫治疗的关系进行简要介绍。     

PD-1/PD-L1免疫抑制剂在非小细胞肺癌免疫治疗中的研究进展

摘 要：近年来免疫检查点领域研究进展迅速,众多新药相继出现,其中包括程序性细胞死亡蛋白1（programmed cell death protein 1,PD-1）单抗Pembrolizumab和Nivolumab,程序性细胞死亡蛋白配体1（programmed cell death protein ligand 1,PD-L1）单抗Atezolizumab。免疫检查点PD-1/PD-L1抑制剂给EGFR突变阳性非小细胞肺癌患者带来更多的生存获益,正逐渐改变国内外EGFR突变阳性晚期非小细胞肺癌的治疗模式。全文对PD-1/PD-L1为靶向的肿瘤免疫治疗在晚期EGFR突变阳性非小细胞肺癌患者治疗中的研究进展进行综述。     

胰腺癌免疫治疗的研究进展

胰腺癌是恶性程度最高的消化系统肿瘤,免疫治疗在胰腺癌领域的研究取得较大进展。目前对免疫检查点的研究主 要集中在细胞毒T淋巴细胞抗原4(cytotoxic T lymphocyte antigen-4,CTLA-4)及程序性细胞死亡分子1 (programmed death-1,PD- 1)/程序性死亡蛋白配体1 (programmed death-ligand 1,PD-L1)等分子的研究。已有大量疫苗应用于胰腺癌：靶向KRas、MUC-1/ CEA、WT1 (Wilms tumor-1) 、热激蛋白、多肽疫苗以及VEGFR2 等,其中取得较好效果的有全肿瘤疫苗(如algenpantucel-L)、端粒 酶多肽疫苗(GV1001)、GVAX瘤苗和WT1疫苗等。T细胞也可以控制胰腺癌的进展,大多数免疫疗法在胰腺癌的临床前期实验 中依靠改进T细胞功能来提高疗效,但未来应用于临床还有待进一步深入研究。     

PD-1/PD-L1在肿瘤免疫逃逸中的作用机制及其临床应用

程序性死亡受体-1 (programmed death receptor-1,PD-1)是T细胞上主要存在的一种抑制性受体,与程序性死亡受体配体-1 (programmed death receptor ligand-1,PD-L1)相互作用,可抑制T细胞增殖、活化.在正常机体中,PD-1/PD-L1信号通路对维持机体的免疫耐受具有重要作用;而在肿瘤发生时,PD-1/PD-L1信号通路能抑制T细胞的免疫反应而促进肿瘤免疫逃逸的发生.本文从PD-1/PD-L1的发现及其结构、信号通路的作用机制、PD-1/PD-L1抗体在肿瘤免疫治疗中的应用等方面进行综述.     

PD-1/PD-L1与食管鳞癌治疗和预后的相关性研究进展

PD-1(programmed cell death-1,程序性死亡受体1)与其配体PD-L1(programmed cell death-ligand 1,程序性死亡配体1) 是一对共刺激分子,对机体免疫反应起负性调节作用.阻断PD-1/PD-L1信号通路可以增强T细胞免疫功能,发挥抗肿瘤作用.目前有研究显示PD-1/PD-L1自身的分子生物学特性及在食管鳞状细胞癌(esophageal squamous cell carcinoma ,ESCC)组织中的表达水平可能与患者的预后有一定的相关性,本文就PD-1/PD-L1的生物结构、分子作用机制以及与ESCC治疗和预后的相关性进行探讨.     

食管鳞癌PD-1/PD-L1分子生物学特点、与治疗和预后的相关性研究进展

PD-1(programmed cell death-1,程序性死亡受体1)与其配体PD-L1(programmed cell death-ligand 1,程序性死亡配体1) 是一对共刺激分子,对机体免疫反应起负性调节作用。阻断PD-1/PD-L1信号通路可以增强T细胞免疫功能,发挥抗肿瘤作用。目前有研究显示PD-1/PD-L1自身的分子生物学特性及在食管鳞状细胞癌（esophageal squamous cell carcinoma ,ESCC）组织中的表达水平可能与患者的预后有一定的相关性,本文就PD-1/PD-L1的生物结构、分子作用机制与ESCC和治疗、预后的相关性进行探讨。     

卡瑞利珠单抗致免疫相关性肠炎1例并文献复习

<正>免疫检查点抑制剂(immune checkpoint inhibitor,ICI)^[1]是目前临床应用广泛的抗肿瘤药物,包括细胞毒性T淋巴细胞相关蛋白4(cytotoxic T lymphocyte antigen 4,CTLA-4)抗体、细胞程序性死亡受体1(programmed cell death receptor 1,PD-1)抗体及程序性死亡配体1(programmed death-ligand1,PD-L1)抗体这几种制剂。随着ICI的广泛使用,越来越多累及皮肤、内分泌、肝脏等的免疫相关性不良反应(immune-related adverse effects,irAEs)^[2-3]被报道,     

PD-1 PD-L1单抗在复发 转移性鼻咽癌中的研究进展

鼻咽癌患者经放疗及同步辅助化疗后,临床转归有所改善,但肿瘤复发及远处转移仍为一项难题。近些年,免疫检查点抑制剂的发现为肿瘤的免疫治疗提供了新的选择。其中,程序性细胞死亡受体1(programmed cell death protein-1,PD-1)/程序性死亡受体配体1(programmed cell death 1-ligand,PD-L1)单抗受到广泛关注且已应用于临床治疗。本文就帕博利珠单抗、纳武利尤单抗、卡瑞利珠单抗和特瑞普利单抗等PD-1/PD-L1单抗在复发/转移性鼻咽癌中的研究进展进行综述。     

抗PD-1/PD-L1疗法致免疫相关不良反应机制及预测标志物的研究进展

抗程序性细胞死亡受体-1(programmed cell death protein-1,PD-1)和抗程序性死亡受体配体-1(programmed cell death ligand-1,PD-L1)是目前广泛使用的免疫检查点抑制剂,在肿瘤免疫治疗方面取得了巨大的成就,但同时也导致免疫相关不良反应(immune-related adverse events, irAEs),严重者甚至会导致患者死亡。因此,明确irAEs的发生机制,提早预测irAEs非常重要。本文由细胞、免疫系统、个体水平层面对抗PD-1/PD-L1疗法致irAEs的发生机制进行了总结,并从一般临床特征、免疫细胞因素、细胞因子相关、基因表达结果等方面汇总了irAEs的预测指标。     

免疫治疗在膀胱癌中的最新研究进展和未来展望

膀胱癌已成为泌尿男生殖系统中常见的恶性肿瘤。自1976年将卡介苗(Bacillus Calmette-Guerin,BCG)膀胱灌注成功地用于非肌层浸润性膀胱癌治疗之后,膀胱癌的治疗未见显著进步,尤其是局部进展和转移性膀胱癌的治疗效果仍不理想。近年来,膀胱癌免疫治疗取得了重大突破,尤其是针对程序性细胞死亡分子1(programmed death-1,PD-1)、程序性细胞死亡分子配体1(programmed death-ligand 1,PD-L1)和细胞毒T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte-associated protein 4,CTLA-4)的免疫检查点抑制剂已被证实不仅具有良好的耐受性,而且能显著改善局部进展和晚期膀胱癌患者的预后。PD-1、PD-L1和CTLA-4抑制剂主要通过阻断负向调控信号,恢复T细胞活性,从而增强T细胞的抗肿瘤免疫应答。其他免疫治疗还包括嵌合抗原受体T细胞免疫疗法(chimeric antigen receptor T-cell immunotherapy,CAR-T)等也具有良好的发展前景。该研究将对免疫治疗在膀胱癌治疗中的作用机制、疗效等进行综述。     

PD-1/PD-L1抑制剂联合治疗在癌症免疫治疗中的研究进展

程序性死亡蛋白-1(programmed cell death-1,PD-1)是一种免疫检查点的负性调控因子,通过与其配体PD-L1/PD-L2结合,抑制T细胞的免疫功能,而PD-1抑制剂则可恢复免疫系统的抗肿瘤作用。较其他治疗手段而言,PD-1抑制剂有显著的临床疗效,然而其仍然存在不足,即目前仍有很大一部分癌症患者对PD-1抑制剂治疗是无效的。研究表明联合治疗可改善PD-1抑制剂单药治疗的有效率。联合治疗包括联合免疫检查点抑制剂、放疗、化疗、癌症疫苗和其他癌症治疗方法。FDA已批准了PD-1抑制剂联合CTLA-4阻断剂治疗,其抗肿瘤效率与肿瘤微环境以及免疫相关因子有关,但关于免疫系统,特别是T细胞对肿瘤阳性响应率的潜在作用机制研究甚少。本文将综述免疫检查点PD-1抑制剂的临床疗效以及其影响因素、作用机制以及PD-1抑制剂联合其他治疗的研究现状。     

PD-1 blockade enhances cytokine-induced killer cell-mediated cytotoxicity in B-cell non-Hodgkin lymphoma cell lines

The clinical utility of immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors used alone or in combination with other therapies, is currently gaining attention. In this particular scenario, the inclusion of cytokine-induced killer (CIK) cells has proven to be a novel therapeutic approach. CIK cells have shown anticancer activity in various hematopoietic malignancies, but their defined cytotoxicity in B-cell non-Hodgkin lymphoma (B-NHL) remains to be fully elucidated. The present study investigated the role of PD-1/PD-L1 blockades on the cytotoxic efficacy of CIK cells primarily in B-NHL cell lines. The current analysis revealed that CIK cells prompted cytotoxicity against B-NHL cell lines (DAUDI and SU-DHL-4), and a significant increase in PD-L1 expression was observed when CIK cells were co-cultured with B-NHL cells. Additionally, a combination of PD-1 and PD-L1 antibodies with CIK cells significantly decreased cell viability only in DAUDI cells. Furthermore, IFN-γ elevation was observed in both cell lines treated with CIK alone or with PD-1 antibody, but this tendency was not observed for PD-L1. Since PD-1 can suppress immune inactivation, whereas CD40L can promote it, the effects of CD40L blockade were also examined; however, no significant changes in cell viability were observed. Overall, the present in vitro data suggested that CIK cells exerted a cytotoxic function in B-NHL cells, and a combination of PD-1 inhibitors with CIK cells may provide a potential therapeutic option for this type of lymphoma. Nevertheless, in vivo experiments are warranted to undermine the extent to which PD-1 inhibitors may be used to enhance the antitumor activity of CIK cells in B-NHL.     

PD-1/PD-L1抑制剂在前列腺癌免疫治疗中的研究进展

前列腺癌（prostate cancer,PCa）发病率呈逐年上升趋势,前列腺癌免疫治疗已成为继外科、放疗、化疗之后的第四种治疗方法。作为当今肿瘤免疫治疗领域最具有研究前景的免疫检查点抑制剂中的程序性死亡受体-1（programmed cell death-1,PD-1）/程序性死亡配体-1（programmed cell death-ligand1,PD-L1）抑制剂,通过阻断PD-1与其配体PD-L1结合,从而终止T细胞的负性调控信号,使T细胞的活性恢复,进而逆转肿瘤免疫逃逸机制,恢复自身免疫应答,最后起到抑制和杀伤肿瘤的作用。本文就目前应用于前列腺癌临床试验的PD-1/PD-L1抑制剂的现况和临床疗效研究进展进行综述。      

免疫检查点在乳腺癌中的研究进展

免疫检查点对于维持自身免疫耐受、避免免疫系统对正常组织进行攻击发挥着至关重要的作用。肿瘤细胞能够利用免疫检查点通路的激活逃避免疫系统的识别。目前最重要的免疫检查点为细胞毒T淋巴细胞相关抗原-4（CTLA-4）、程序性死亡受体-1（PD-1）及程序性死亡受体配体-1（PD-L1）。肿瘤细胞PD-L1通过与活化的T细胞的PD-1结合,能够通过诱导T细胞的凋亡降低肿瘤免疫反应。免疫检查点抑制剂的应用能够延长肿瘤患者的生存时间。尽管目前对于免疫检查点认识有限,但免疫检查点抑制剂作为新的治疗方法有望改变乳腺癌的治疗模式。本篇综述将介绍乳腺癌中免疫检查点的研究进展。     

Current situation of programmed cell death protein 1/programmed cell death ligand 1 inhibitors in advanced triple-negative breast cancer

Triple-negative breast cancer(TNBC) has the worst prognosis among all molecular types of breast cancer. Because of the strong immunogenicity of TNBC cells, programmed death 1/programmed death ligand 1(PD-1/PD-L1)inhibitors, two kinds of immune checkpoint blockade agents, might help improve the prognosis of TNBC.However, how to better use PD-1/PD-L1 inhibitors and select patients who may benefit from treatment options remains controversial. This article summarizes published clinical studies in wh...     

The evolving role of PD-L1 testing in patients with metastatic urothelial carcinoma

Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway improve clinical outcomes in patients with locally advanced/metastatic urothelial carcinoma (UC). PD-L1 complementary or companion diagnostic assays are now available for anti–PD-1 and anti–PD-L1 antibodies and these assays enable testing at diagnosis. The role of PD-L1 testing in UC is, however, the subject of much discussion within the medical community, particularly in light of recent restrictions on recruitment of PD-L1–low patients in clinical trials of atezolizumab and pembrolizumab as first-line therapy, and the European Medicines Agency and US Food and Drug Administration limiting use of these agents as first-line therapy in cisplatin-ineligible patients to those with high PD-L1 expression. We explore the evolving evidence for PD-L1 expression testing in UC and the role of PD-L1 expression in both tumor cells and tumor-infiltrating immune cells. We review clinical data on the prognostic and predictive value of PD-L1 expression in response to anti–PD-1/PD-L1 agents as first- and second-line therapy, considering issues such as the differences among complementary diagnostic assays in terms of the type of cells scored, antibodies used, and cutoff values. We consider how PD-L1 testing fits into decision-making and the potential of emerging biomarkers in UC. We conclude that, based on the scientific rationale for its use and evidence from clinical trials, PD-L1 testing provides enriched information on the patients most likely to benefit from immune checkpoint blockade and should be routinely offered to patients with metastatic UC.     

树突状细胞和PD-1/PD-L1通路相互作用的研究进展

树突状细胞（dendritic cells,DCs）是最强大的抗原呈递细胞,具有引起抗原特异性反应的能力,并且在调节免疫耐受中起重要作用。基于DCs的癌症免疫治疗已有二十多年的研究,是最重要的抗癌免疫疗法之一,但单一疗法在癌症治疗方面效果有限,需要继续深入研究以提高DCs的抗肿瘤作用,并寻找与其他方法协同治疗的方案。靶向于免疫检查点的单克隆抗体在公认的实体和血液恶性肿瘤的临床试验中均获得了成功,并在2018年获得诺贝尔医学奖。免疫检查点阻断疗法旨在解除肿瘤的免疫抑制以增强免疫系统的抗肿瘤作用,其中针对PD-1/PD-L1免疫检查点的阻断治疗已引起相当多的关注。虽然免疫检查点阻断治疗的效果令人鼓舞,但在尚未满足医疗需求的领域中仍需要进一步研究以提高临床效率。理论上DCs的PD-L1和/或T细胞的PD-1基因沉默或表达下调,可增强DCs启动有效的T细胞抗肿瘤反应。因此,将特异性DCs的抗肿瘤免疫治疗与PD-1/PD-L1信号通路阻断相结合的治疗方法是一个有希望的探索之路。本文主要综述DCs的功能、PD-1/PD-L1通路的抗肿瘤作用、DCs和PD-1/PD-L1信号通路相互作用在目前的研究现状以及前景。     

免疫检查点PD-1／PD-L1通路在小细胞肺癌中的作用

小细胞肺癌（SCLC）主要的特点为生长迅速且早期易发生广泛转移。尽管SCLC对于化疗和放疗敏感,但几乎所有的患者均在治疗后发生复发转移,预后差。免疫检测点抑制剂,尤其程序化细胞死亡受体-1（PD-1）／程序化细胞死亡配体-1（PD-L1）拮抗剂在SCLC的临床前和临床研究中均获得了良好效果,并且能够延长患者生存。免疫检测点疗法作为一种新兴的方法在未来可能会改变SCLC治疗模式。此外,有限的数据显示出PD-L1表达可能成为筛选获益人群一个有效的生物标记物。本文总结PD-L1作为标记物的发展历程,并同时阐述PD-1／PD-L1抑制剂在SCLC治疗中的进展。     

Combination Treatment of the Oral CHK1 Inhibitor,SRA737, and Low-Dose Gemcitabine Enhances the Effect of Programmed Death Ligand 1 Blockade by Modulating the Immune Microenvironment in SCLC

IntroductionDespite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC.Methods and ResultsHere, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti–programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti–PD-L1/anti–PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNβ, and chemokines, CCL5 and CXCL10.ConclusionsGiven that anti–PD-L1/anti–PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.     

PD-1/PD-L1抑制剂治疗淋巴瘤的研究进展

免疫检查点抑制剂已被批准用于多种难治性实体肿瘤的治疗,如恶性黑色素瘤、肺癌、胰腺癌、肾癌等。其在复发/难治性淋巴瘤的治疗方面也展现出广阔的应用前景。程序性死亡受体-1及其配体(PD-1/PD-L1)通路是免疫检查点抑制治疗(checkpoint blockade therapy,CBT)的关键性通路之一。肿瘤细胞可通过PD-1/PD-L1通路抑制T细胞活性,阻断免疫应答,从而实现免疫逃逸,最终促进肿瘤的发生、发展。新近研究发现PD-1/PD-L1通路在复发/难治性霍奇金淋巴瘤（Hodgkin lymphoma,HL）和部分非霍奇金淋巴瘤（non-Hodgkin lymphoma,NHL）中也发挥着重要作用。本文将简单介绍PD-1/PD-L1通路的生物学活性,总结针对该通路的免疫疗法在恶性淋巴瘤治疗中的研究进展。