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活动中心 前沿资讯 PD-1/PD-L1通路实现免疫逃逸的机制是什么?
<html> <head></head> <body> <div style=""> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">免疫检查点(</span><span style="font-family:'Roboto';color:#202530;">immune checkpoints</span><span style="font-family:'Roboto';color:#202530;">)是调节免疫系统的关键分子,它们通过控制免疫反应的强度和持续时间,维持免疫系统的平衡。这些检查点通常起到</span><span style="font-family:'Roboto';color:#202530;">“</span><span style="font-family:'Roboto';color:#202530;">刹车</span><span style="font-family:'Roboto';color:#202530;">”</span><span style="font-family:'Roboto';color:#202530;">作用,防止免疫系统过度活跃,从而避免对自身组织的攻击,维持免疫耐受。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">早在</span><span style="font-family:'Roboto';color:#202530;">20</span><span style="font-family:'Roboto';color:#202530;">世纪</span><span style="font-family:'Roboto';color:#202530;">90</span><span style="font-family:'Roboto';color:#202530;">年代,免疫学家</span><span style="font-family:'Roboto';color:#202530;">James P. Allison</span><span style="font-family:'Roboto';color:#202530;">和</span><span style="font-family:'Roboto';color:#202530;">Tasuku</span><span style="font-family:'Roboto';color:#202530;"> </span><span style="font-family:'Roboto';color:#202530;">Honjo</span><span style="font-family:'Roboto';color:#202530;">分别发现了</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞上的两种刹车分子</span><span style="font-family:'Roboto';color:#202530;">——CTLA-4</span><span style="font-family:'Roboto';color:#202530;">和</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">,并提出免疫检查点抑制可重新激活</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞,更有效地消灭癌细胞,因此获得了</span><span style="font-family:'Roboto';color:#202530;">2018</span><span style="font-family:'Roboto';color:#202530;">年的诺贝尔生理学或医学奖。越来越多的研究也显示,免疫检查点抑制剂(</span><span style="font-family:'Roboto';color:#202530;">ICB</span><span style="font-family:'Roboto';color:#202530;">)具有显著的治疗价值。</span></p> <p style="text-align:left;margin-top:15.0pt;margin-bottom:7.0pt;"><span style="font-family:'Roboto';font-size:22.0pt;font-weight:bold;color:#202530;">什么是</span><span style="font-family:'Roboto';font-size:22.0pt;font-weight:bold;color:#202530;">PD-1/PD-L1</span><span style="font-family:'Roboto';font-size:22.0pt;font-weight:bold;color:#202530;">通路?</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">程序性死亡受体</span><span style="font-family:'Roboto';color:#202530;">-1</span><span style="font-family:'Roboto';color:#202530;">(</span><span style="font-family:'Roboto';color:#202530;">PD-1 </span><span style="font-family:'Roboto';color:#202530;">;也称</span><span style="font-family:'Roboto';color:#202530;">CD279</span><span style="font-family:'Roboto';color:#202530;">)是免疫检查点之一,通过与其配体</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">(也称</span><span style="font-family:'Roboto';color:#202530;">B7-H1/CD274</span><span style="font-family:'Roboto';color:#202530;">)或</span><span style="font-family:'Roboto';color:#202530;">PD-L2</span><span style="font-family:'Roboto';color:#202530;">(也称</span><span style="font-family:'Roboto';color:#202530;">B7-DC/CD273</span><span style="font-family:'Roboto';color:#202530;">)的作用负责</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞的激活、增殖和细胞毒性分泌,控制着肿瘤微环境中免疫耐受的诱导和维持。利用抗</span><span style="font-family:'Roboto';color:#202530;">PD-1/PD-L1</span><span style="font-family:'Roboto';color:#202530;">的单克隆抗体阻断</span><span style="font-family:'Roboto';color:#202530;">PD-1/PD-L1</span><span style="font-family:'Roboto';color:#202530;">信号通路,已在多种实体瘤中显示出卓越的抗肿瘤疗效。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"> <div style="background: #FFFFFF; box-shadow: 0px 6px 17px 0px rgba(189,192,196,0.35); padding: 24px; max-width:100%;border-radius: 10px; text-align: center;"> <img src="https://cdn.targetmol.cn/group3/M00/3F/94/CgoaEGfg1AqEMbVXAAAAABlSwOc87.webp" style="max-width: 100%;" /> </div></p> <p style="text-align:left;margin-top:15.0pt;margin-bottom:7.0pt;"><span style="font-family:'Roboto';font-size:18.0pt;font-weight:bold;color:#202530;">PD-1</span><span style="font-family:'Roboto';font-size:18.0pt;font-weight:bold;color:#202530;">的表达与调控</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">是一个</span><span style="font-family:'Roboto';color:#202530;">55 </span><span style="font-family:'Roboto';color:#202530;">kDa</span><span style="font-family:'Roboto';color:#202530;">的跨膜蛋白,含有</span><span style="font-family:'Roboto';color:#202530;">288</span><span style="font-family:'Roboto';color:#202530;">个氨基酸,在</span><span style="font-family:'Roboto';color:#202530;">1992</span><span style="font-family:'Roboto';color:#202530;">年于缺乏白细胞介素</span><span style="font-family:'Roboto';color:#202530;">-3</span><span style="font-family:'Roboto';color:#202530;">(</span><span style="font-family:'Roboto';color:#202530;">IL-3</span><span style="font-family:'Roboto';color:#202530;">)的</span><span style="font-family:'Roboto';color:#202530;">LyD9</span><span style="font-family:'Roboto';color:#202530;">(小鼠造血祖细胞)和</span><span style="font-family:'Roboto';color:#202530;">2B4-11</span><span style="font-family:'Roboto';color:#202530;">(小鼠</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞杂交瘤)细胞系中首次被发现,是一种适应性和先天免疫反应的抑制因子,主要在活化的</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞、自然杀伤细胞(</span><span style="font-family:'Roboto';color:#202530;">NK</span><span style="font-family:'Roboto';color:#202530;">)、</span><span style="font-family:'Roboto';color:#202530;">B</span><span style="font-family:'Roboto';color:#202530;">淋巴细胞、巨噬细胞、树突状细胞(</span><span style="font-family:'Roboto';color:#202530;">DC</span><span style="font-family:'Roboto';color:#202530;">)以及单核细胞上表达。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">在正常的生理条件下,</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞几乎不表达</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">,只有当</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞长期暴露于抗原刺激被活化后,</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">的表达才会被上调。这个过程由多种转录因子如</span><span style="font-family:'Roboto';color:#202530;">NFAT</span><span style="font-family:'Roboto';color:#202530;">、</span><span style="font-family:'Roboto';color:#202530;">NOTCH</span><span style="font-family:'Roboto';color:#202530;">、</span><span style="font-family:'Roboto';color:#202530;">FOX 01</span><span style="font-family:'Roboto';color:#202530;">和</span><span style="font-family:'Roboto';color:#202530;">IRF9</span><span style="font-family:'Roboto';color:#202530;">等调控,如果激活抗原被快速清除,</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">水平会在响应的</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞上降低。然而,如果抗原未被清除(如在慢性感染和癌症中),</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">会持续高表达。</span></p> <p style="text-align:left;margin-top:15.0pt;margin-bottom:7.0pt;"><span style="font-family:'Roboto';font-size:18.0pt;font-weight:bold;color:#202530;">PD-L1</span><span style="font-family:'Roboto';font-size:18.0pt;font-weight:bold;color:#202530;">的表达与调控</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">是</span><span style="font-family:'Roboto';color:#202530;">B7</span><span style="font-family:'Roboto';color:#202530;">系列的一种</span><span style="font-family:'Roboto';color:#202530;">33 </span><span style="font-family:'Roboto';color:#202530;">kDa</span><span style="font-family:'Roboto';color:#202530;">的</span><span style="font-family:'Roboto';color:#202530;">I</span><span style="font-family:'Roboto';color:#202530;">型跨膜糖蛋白,含有</span><span style="font-family:'Roboto';color:#202530;">290</span><span style="font-family:'Roboto';color:#202530;">个氨基酸。</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">通常由巨噬细胞、一些活化的</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞和</span><span style="font-family:'Roboto';color:#202530;">B</span><span style="font-family:'Roboto';color:#202530;">细胞、树突状细胞(</span><span style="font-family:'Roboto';color:#202530;">DCs</span><span style="font-family:'Roboto';color:#202530;">)以及一些上皮细胞在炎症条件下表达。此外,肿瘤细胞也会表达</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">,作为一种</span><span style="font-family:'Roboto';color:#202530;">“</span><span style="font-family:'Roboto';color:#202530;">适应性免疫机制</span><span style="font-family:'Roboto';color:#202530;">”</span><span style="font-family:'Roboto';color:#202530;">以逃避抗肿瘤反应。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的表达和调控机制非常复杂,涉及多种不同的因素以及信号通路。有研究把</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的表达和调控大致分为了两类:</span></p> <p style="text-align:left;"><span style="font-family:'Roboto';font-weight:bold;color:#202530;">主要机制(非免疫驱动):包括</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">(1) </span><span style="font-family:'Roboto';color:#202530;">基因组异常:</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的表达可由于基因的突变、扩增或重排导致。例如,某些肿瘤中存在的</span><span style="font-family:'Roboto';color:#202530;">EML4-ALK</span><span style="font-family:'Roboto';color:#202530;">融合基因可以通过</span><span style="font-family:'Roboto';color:#202530;">MEK/ERK</span><span style="font-family:'Roboto';color:#202530;">和</span><span style="font-family:'Roboto';color:#202530;">PI3K/Akt</span><span style="font-family:'Roboto';color:#202530;">信号通路上调</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的表达。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">(2) </span><span style="font-family:'Roboto';color:#202530;">基于</span><span style="font-family:'Roboto';color:#202530;">microRNA</span><span style="font-family:'Roboto';color:#202530;">的调控:</span><span style="font-family:'Roboto';color:#202530;">microRNA</span><span style="font-family:'Roboto';color:#202530;">可以通过结合到</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的</span><span style="font-family:'Roboto';color:#202530;">mRNA</span><span style="font-family:'Roboto';color:#202530;">上调控其表达。例如,</span><span style="font-family:'Roboto';color:#202530;">miR-142-5p</span><span style="font-family:'Roboto';color:#202530;">可下调</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的表达。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">(3) </span><span style="font-family:'Roboto';color:#202530;">致癌转录因子和通路:</span><span style="font-family:'Roboto';color:#202530;">MYC</span><span style="font-family:'Roboto';color:#202530;">、</span><span style="font-family:'Roboto';color:#202530;">STATs</span><span style="font-family:'Roboto';color:#202530;">、</span><span style="font-family:'Roboto';color:#202530;">NF-</span><span style="font-family:'Roboto';color:#202530;">κB</span><span style="font-family:'Roboto';color:#202530;">、</span><span style="font-family:'Roboto';color:#202530;">HIF1α/2α</span><span style="font-family:'Roboto';color:#202530;">等转录因子可以通过各种信号通路(如</span><span style="font-family:'Roboto';color:#202530;">RAS/MEK/ERK</span><span style="font-family:'Roboto';color:#202530;">,</span><span style="font-family:'Roboto';color:#202530;">PI3K/Akt/mTOR</span><span style="font-family:'Roboto';color:#202530;">,</span><span style="font-family:'Roboto';color:#202530;">JAK/STATs</span><span style="font-family:'Roboto';color:#202530;">和</span><span style="font-family:'Roboto';color:#202530;">TLRs/IKKs</span><span style="font-family:'Roboto';color:#202530;">)影响</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的表达。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">(4) </span><span style="font-family:'Roboto';color:#202530;">翻译后调控和转运:</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的蛋白表达也受到翻译后修饰的调控,包括泛素化、去泛素化、磷酸化、糖基化和棕榈酰化。例如,</span><span style="font-family:'Roboto';color:#202530;">GSK3β</span><span style="font-family:'Roboto';color:#202530;">与</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">相互作用并诱导其磷酸化和随后的泛素化依赖性降解。</span></p> <p style="text-align:left;"><span style="font-family:'Roboto';font-weight:bold;color:#202530;">次要机制(免疫驱动):</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">主要由肿瘤微环境(</span><span style="font-family:'Roboto';color:#202530;">TME</span><span style="font-family:'Roboto';color:#202530;">)中的免疫细胞产生的可溶性因子驱动的炎症信号激活。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">例如,多种可溶性细胞因子可以诱导</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的表达,</span><span style="font-family:'Roboto';color:#202530;">IFN-γ</span><span style="font-family:'Roboto';color:#202530;">正是之一。早期研究指出,</span><span style="font-family:'Roboto';color:#202530;">IFN-γ</span><span style="font-family:'Roboto';color:#202530;">可以调控多种肿瘤类型、健康组织和免疫细胞中的</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">表达。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"> <div style="background: #FFFFFF; box-shadow: 0px 6px 17px 0px rgba(189,192,196,0.35); padding: 24px; max-width:100%;border-radius: 10px; text-align: center;"> <img src="https://cdn.targetmol.cn/group3/M00/3F/94/CgoaEGfg1AqEVu3SAAAAAAAeoRU10.webp" style="max-width: 100%;" /> </div></p> <p style="text-align:center;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的表达调控</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">&nbsp;</span></p> <p style="text-align:left;margin-top:15.0pt;margin-bottom:7.0pt;"><span style="font-family:'Roboto';font-size:22.0pt;font-weight:bold;color:#202530;">PD-1/PD-L1</span><span style="font-family:'Roboto';font-size:22.0pt;font-weight:bold;color:#202530;">通路如何实现免疫逃逸的机制?</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">许多肿瘤细胞上调</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">的表达,以应对宿主的免疫压力。</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">可以与</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞上的</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">结合,传递抑制性信号,使</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞失去杀伤活性。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">与</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">结合后,</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞内的磷酸化事件会被抑制,影响</span><span style="font-family:'Roboto';color:#202530;">TCR</span><span style="font-family:'Roboto';color:#202530;">(</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞受体)的信号传导。这导致</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞活性降低,细胞周期停滞,甚至诱导</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞凋亡。</span><span style="font-family:'Roboto';color:#202530;">PD-1/PD-L1</span><span style="font-family:'Roboto';color:#202530;">通路的活化还会抑制</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞向肿瘤部位的迁移和浸润,使得肿瘤微环境中有效的</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞数量减少。</span></p> <p style="text-align:center;margin-bottom:7.0pt;"> <div style="background: #FFFFFF; box-shadow: 0px 6px 17px 0px rgba(189,192,196,0.35); padding: 24px; max-width:100%;border-radius: 10px; text-align: center;"> <img src="https://cdn.targetmol.cn/group3/M00/3F/91/CgoaEWfg1AqEZlamAAAAALhU8Nk85.webp" style="max-width: 100%;" /> </div></p> <p style="text-align:center;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">介导的</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞抑制机制</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">具体来说,</span><span style="font-family:'Roboto';color:#202530;">PD-L1/PD-L2</span><span style="font-family:'Roboto';color:#202530;">与</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">结合后,会招募磷酸酶</span><span style="font-family:'Roboto';color:#202530;">SHP-2</span><span style="font-family:'Roboto';color:#202530;">,削弱</span><span style="font-family:'Roboto';color:#202530;">LCK</span><span style="font-family:'Roboto';color:#202530;">诱导的</span><span style="font-family:'Roboto';color:#202530;">ZAP70</span><span style="font-family:'Roboto';color:#202530;">磷酸化,并减少</span><span style="font-family:'Roboto';color:#202530;">RAS-MEK-ERK/PI3K-Akt-mTOR</span><span style="font-family:'Roboto';color:#202530;">通路的活性。此外,</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">的激活会诱导</span><span style="font-family:'Roboto';color:#202530;">BATF</span><span style="font-family:'Roboto';color:#202530;">的表达,抑制效应基因的表达。总体而言,</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">信号通路导致</span><span style="font-family:'Roboto';color:#202530;">T</span><span style="font-family:'Roboto';color:#202530;">细胞的增殖、激活、效应功能和存活受到抑制。</span></p> <p style="text-align:left;margin-top:15.0pt;margin-bottom:7.0pt;"><span style="font-family:'Roboto';font-size:22.0pt;font-weight:bold;color:#202530;">PD-1/PD-L1</span><span style="font-family:'Roboto';font-size:22.0pt;font-weight:bold;color:#202530;">抑制剂</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">目前已有多种</span><span style="font-family:'Roboto';color:#202530;">PD-1/PD-L1</span><span style="font-family:'Roboto';color:#202530;">抑制剂被发现在癌症中起着关键作用,例如:</span></p> <p style="text-align:left;"><a href="https://www.targetmol.cn/compound/Pembrolizumab" rel="noopener noreferrer nofollow"><span style="font-family:'Roboto';font-style:italic;color:#0000ff;">Pembrolizumab</span> </a></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">pembrolizumab </span><span style="font-family:'Roboto';color:#202530;">是一种高度选择性的</span><span style="font-family:'Roboto';color:#202530;"> IgG4-kappa </span><span style="font-family:'Roboto';color:#202530;">人源化单克隆抗体,靶向</span><span style="font-family:'Roboto';color:#202530;"> PD-1 </span><span style="font-family:'Roboto';color:#202530;">受体。它通过将一种高亲和力的小鼠抗人</span><span style="font-family:'Roboto';color:#202530;"> PD-1 </span><span style="font-family:'Roboto';color:#202530;">抗体的可变序列移植到含有稳定</span><span style="font-family:'Roboto';color:#202530;"> S228P Fc </span><span style="font-family:'Roboto';color:#202530;">突变的人类</span><span style="font-family:'Roboto';color:#202530;"> IgG4-kappa </span><span style="font-family:'Roboto';color:#202530;">同种型中生成。由默克公司开发,并于</span><span style="font-family:'Roboto';color:#202530;"> 2014 </span><span style="font-family:'Roboto';color:#202530;">年</span><span style="font-family:'Roboto';color:#202530;"> 9 </span><span style="font-family:'Roboto';color:#202530;">月</span><span style="font-family:'Roboto';color:#202530;"> 4 </span><span style="font-family:'Roboto';color:#202530;">日获得</span><span style="font-family:'Roboto';color:#202530;"> FDA </span><span style="font-family:'Roboto';color:#202530;">批准,用于治疗转移性恶性黑色素瘤,也是首个获得批准的</span><span style="font-family:'Roboto';color:#202530;"> PD-1 </span><span style="font-family:'Roboto';color:#202530;">抗体疗法。自首次批准以来,</span><span style="font-family:'Roboto';color:#202530;">pembrolizumab </span><span style="font-family:'Roboto';color:#202530;">已获得批准用于治疗多种癌症。</span></p> <p style="text-align:left;"><a href="https://www.targetmol.cn/compound/Nivolumab" rel="noopener noreferrer nofollow"><span style="font-family:'Roboto';font-style:italic;color:#0000ff;">Nivolumab</span> </a></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">nivolumab </span><span style="font-family:'Roboto';color:#202530;">是一种人源化</span><span style="font-family:'Roboto';color:#202530;"> IgG4 </span><span style="font-family:'Roboto';color:#202530;">抗体,靶向</span><span style="font-family:'Roboto';color:#202530;">PD-1</span><span style="font-family:'Roboto';color:#202530;">。该抗体最初在小鼠中完全生产,然后移植到人类的</span><span style="font-family:'Roboto';color:#202530;"> kappa </span><span style="font-family:'Roboto';color:#202530;">和</span><span style="font-family:'Roboto';color:#202530;"> IgG4 Fc </span><span style="font-family:'Roboto';color:#202530;">区域,并进行了</span><span style="font-family:'Roboto';color:#202530;"> S228P </span><span style="font-family:'Roboto';color:#202530;">突变,以提高稳定性。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">nivolumab </span><span style="font-family:'Roboto';color:#202530;">于</span><span style="font-family:'Roboto';color:#202530;"> 2014 </span><span style="font-family:'Roboto';color:#202530;">年</span><span style="font-family:'Roboto';color:#202530;"> 12 </span><span style="font-family:'Roboto';color:#202530;">月</span><span style="font-family:'Roboto';color:#202530;"> 22 </span><span style="font-family:'Roboto';color:#202530;">日获得</span><span style="font-family:'Roboto';color:#202530;"> FDA </span><span style="font-family:'Roboto';color:#202530;">批准上市。它也可以与</span><span style="font-family:'Roboto';color:#202530;"> </span><span style="font-family:'Roboto';color:#202530;">relatlimab</span><span style="font-family:'Roboto';color:#202530;"> </span><span style="font-family:'Roboto';color:#202530;">联合使用,品牌名为</span><span style="font-family:'Roboto';color:#202530;"> </span><span style="font-family:'Roboto';color:#202530;">Opdualag</span><span style="font-family:'Roboto';color:#202530;">。</span></p> <p style="text-align:left;"><a href="https://www.targetmol.cn/compound/Atezolizumab" rel="noopener noreferrer nofollow"><span style="font-family:'Roboto';font-style:italic;color:#0000ff;">Atezolizumab</span> </a></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">atezolizumab </span><span style="font-family:'Roboto';color:#202530;">能够阻断</span><span style="font-family:'Roboto';color:#202530;"> PD-L1 </span><span style="font-family:'Roboto';color:#202530;">与其受体</span><span style="font-family:'Roboto';color:#202530;"> PD-1 </span><span style="font-family:'Roboto';color:#202530;">和</span><span style="font-family:'Roboto';color:#202530;"> B7.1 </span><span style="font-family:'Roboto';color:#202530;">之间的相互作用,从而增强</span><span style="font-family:'Roboto';color:#202530;"> T </span><span style="font-family:'Roboto';color:#202530;">细胞介导的抗肿瘤免疫。</span><span style="font-family:'Roboto';color:#202530;">atezolizumab </span><span style="font-family:'Roboto';color:#202530;">单药治疗已获批准用于转移性尿路上皮癌(</span><span style="font-family:'Roboto';color:#202530;">UC</span><span style="font-family:'Roboto';color:#202530;">)和非小细胞肺癌(</span><span style="font-family:'Roboto';color:#202530;">NSCLC</span><span style="font-family:'Roboto';color:#202530;">)。</span></p> <p style="text-align:left;"><a href="https://www.targetmol.cn/compound/Avelumab" rel="noopener noreferrer nofollow"><span style="font-family:'Roboto';font-style:italic;color:#0000ff;">Avelumab</span> </a></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">avelumab </span><span style="font-family:'Roboto';color:#202530;">能够结合</span><span style="font-family:'Roboto';color:#202530;">PD-L1</span><span style="font-family:'Roboto';color:#202530;">,阻断其与</span><span style="font-family:'Roboto';color:#202530;"> T </span><span style="font-family:'Roboto';color:#202530;">细胞和抗原呈递细胞上受体的相互作用。</span><span style="font-family:'Roboto';color:#202530;">avelumab </span><span style="font-family:'Roboto';color:#202530;">于</span><span style="font-family:'Roboto';color:#202530;"> 2017 </span><span style="font-family:'Roboto';color:#202530;">年</span><span style="font-family:'Roboto';color:#202530;"> 3 </span><span style="font-family:'Roboto';color:#202530;">月</span><span style="font-family:'Roboto';color:#202530;"> 23 </span><span style="font-family:'Roboto';color:#202530;">日首次获得</span><span style="font-family:'Roboto';color:#202530;"> FDA </span><span style="font-family:'Roboto';color:#202530;">批准。同年</span><span style="font-family:'Roboto';color:#202530;"> 9 </span><span style="font-family:'Roboto';color:#202530;">月</span><span style="font-family:'Roboto';color:#202530;"> 18 </span><span style="font-family:'Roboto';color:#202530;">日和</span><span style="font-family:'Roboto';color:#202530;"> 12 </span><span style="font-family:'Roboto';color:#202530;">月</span><span style="font-family:'Roboto';color:#202530;"> 18 </span><span style="font-family:'Roboto';color:#202530;">日,分别获得了欧洲药品管理局(</span><span style="font-family:'Roboto';color:#202530;">EMA</span><span style="font-family:'Roboto';color:#202530;">)和加拿大卫生部的批准。它用于治疗梅克尔细胞癌、转移性尿路上皮癌或肾细胞癌。</span></p> <p style="text-align:left;"><a href="https://www.targetmol.cn/compound/cemiplimab" rel="noopener noreferrer nofollow"><span style="font-family:'Roboto';font-style:italic;color:#0000ff;">Cemiplimab</span> </a></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">cemiplimab</span><span style="font-family:'Roboto';color:#202530;"> </span><span style="font-family:'Roboto';color:#202530;">通过阻断</span><span style="font-family:'Roboto';color:#202530;"> PD-1</span><span style="font-family:'Roboto';color:#202530;">,旨在增强</span><span style="font-family:'Roboto';color:#202530;"> T </span><span style="font-family:'Roboto';color:#202530;">细胞介导的抗肿瘤反应。于</span><span style="font-family:'Roboto';color:#202530;"> 2018 </span><span style="font-family:'Roboto';color:#202530;">年</span><span style="font-family:'Roboto';color:#202530;"> 9 </span><span style="font-family:'Roboto';color:#202530;">月</span><span style="font-family:'Roboto';color:#202530;"> 28 </span><span style="font-family:'Roboto';color:#202530;">日首次获得</span><span style="font-family:'Roboto';color:#202530;"> FDA </span><span style="font-family:'Roboto';color:#202530;">批准,成为首个</span><span style="font-family:'Roboto';color:#202530;"> FDA </span><span style="font-family:'Roboto';color:#202530;">批准用于治疗晚期皮肤鳞状细胞癌(</span><span style="font-family:'Roboto';color:#202530;">CSCC</span><span style="font-family:'Roboto';color:#202530;">)的药物。随后,它也获得了用于基底细胞癌和非小细胞肺癌的批准。</span><span style="font-family:'Roboto';color:#202530;">2022 </span><span style="font-family:'Roboto';color:#202530;">年</span><span style="font-family:'Roboto';color:#202530;"> 10 </span><span style="font-family:'Roboto';color:#202530;">月,欧洲药品管理局(</span><span style="font-family:'Roboto';color:#202530;">EMA</span><span style="font-family:'Roboto';color:#202530;">)药品委员会(</span><span style="font-family:'Roboto';color:#202530;">CHMP</span><span style="font-family:'Roboto';color:#202530;">)推荐将</span><span style="font-family:'Roboto';color:#202530;"> </span><span style="font-family:'Roboto';color:#202530;">cemiplimab</span><span style="font-family:'Roboto';color:#202530;"> </span><span style="font-family:'Roboto';color:#202530;">批准用于治疗宫颈癌。</span></p> <p style="text-align:left;margin-bottom:7.0pt;"><span style="font-family:'Roboto';color:#202530;">除此之外,</span><span style="font-family:'Roboto';color:#202530;">TargetMol</span><span style="font-family:'Roboto';color:#202530;">还可提供多种</span><span style="font-family:'Roboto';color:#202530;"> PD-1/PD-L1</span><span style="font-family:'Roboto';color:#202530;">抑制剂、抗体,助力您的研究,欢迎</span><span style="font-family:'Roboto';color:#202530;"> </span><span style="font-family:'Roboto';color:#202530;">私信咨询</span><span style="font-family:'Roboto';color:#202530;">~</span></p> <p style="text-align:left;margin-bottom:7.0pt;"> <div style="background: #FFFFFF; box-shadow: 0px 6px 17px 0px rgba(189,192,196,0.35); padding: 24px; max-width:100%;border-radius: 10px; text-align: center;"> <img src="https://cdn.targetmol.cn/group3/M00/3F/91/CgoaEWfg1AqEMks1AAAAAKnSMaY53.webp" style="max-width: 100%;" /> </div></p> <p style="text-align:left;"><span style="font-family:'Roboto';color:#202530;">参考资料:</span></p> <p style="text-align:left;"><span style="font-family:'Roboto';color:#202530;">Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond.&nbsp;</span><span style="font-family:'Roboto';font-style:italic;color:#202530;">Adv Exp Med Biol</span><span style="font-family:'Roboto';color:#202530;">. </span><span style="font-family:'Roboto';color:#202530;">2020;1248:33</span><span style="font-family:'Roboto';color:#202530;">-59. doi:10.1007/978-981-15-3266-5_3</span></p> <p style="text-align:left;"><span style="font-family:'Roboto';color:#202530;">Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer.&nbsp;</span><span style="font-family:'Roboto';font-style:italic;color:#202530;">Am J Cancer Res</span><span style="font-family:'Roboto';color:#202530;">. 2020;10(3):727-742. Published 2020 Mar 1.</span></p> <p style="text-align:left;"><span style="font-family:'Roboto';color:#202530;">Kleffel</span><span style="font-family:'Roboto';color:#202530;"> S, </span><span style="font-family:'Roboto';color:#202530;">Posch</span><span style="font-family:'Roboto';color:#202530;"> C, Barthel SR, et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth.&nbsp;</span><span style="font-family:'Roboto';font-style:italic;color:#202530;">Cell</span><span style="font-family:'Roboto';color:#202530;">. 2015;162(6):1242-1256. </span><span style="font-family:'Roboto';color:#202530;">doi:10.1016/j.cell</span><span style="font-family:'Roboto';color:#202530;">.2015.08.052</span></p> <p style="text-align:left;"><span style="font-family:'Roboto';color:#202530;">Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800</span></p> <p style="text-align:left;"><a href="https://en.wikipedia.org/wiki/Immune_checkpoint" rel="noopener noreferrer nofollow"><span style="font-family:'Roboto';color:#0000ff;text-decoration:underline;">https://en.wikipedia.org/wiki/Immune_checkpoint</span> </a></p> <p style="text-align:left;"><a href="https://go.drugbank.com/" rel="noopener noreferrer nofollow"><span style="font-family:'Roboto';color:#0000ff;text-decoration:underline;">https://go.drugbank.com/</span> </a></p> <p></p> </div> </body> </html>

免疫检查点(immune checkpoints)是调节免疫系统的关键分子,它们通过控制免疫反应的强度和持续时间,维持免疫系统的平衡。这些检查点通常起到刹车作用,防止免疫系统过度活跃,从而避免对自身组织的攻击,维持免疫耐受。

早在20世纪90年代,免疫学家James P. AllisonTasuku Honjo分别发现了T细胞上的两种刹车分子——CTLA-4PD-1,并提出免疫检查点抑制可重新激活T细胞,更有效地消灭癌细胞,因此获得了2018年的诺贝尔生理学或医学奖。越来越多的研究也显示,免疫检查点抑制剂(ICB)具有显著的治疗价值。

什么是PD-1/PD-L1通路?

程序性死亡受体-1PD-1 ;也称CD279)是免疫检查点之一,通过与其配体PD-L1(也称B7-H1/CD274)或PD-L2(也称B7-DC/CD273)的作用负责T细胞的激活、增殖和细胞毒性分泌,控制着肿瘤微环境中免疫耐受的诱导和维持。利用抗PD-1/PD-L1的单克隆抗体阻断PD-1/PD-L1信号通路,已在多种实体瘤中显示出卓越的抗肿瘤疗效。

PD-1的表达与调控

PD-1是一个55 kDa的跨膜蛋白,含有288个氨基酸,在1992年于缺乏白细胞介素-3IL-3)的LyD9(小鼠造血祖细胞)和2B4-11(小鼠T细胞杂交瘤)细胞系中首次被发现,是一种适应性和先天免疫反应的抑制因子,主要在活化的T细胞、自然杀伤细胞(NK)、B淋巴细胞、巨噬细胞、树突状细胞(DC)以及单核细胞上表达。

在正常的生理条件下,T细胞几乎不表达PD-1,只有当T细胞长期暴露于抗原刺激被活化后,PD-1的表达才会被上调。这个过程由多种转录因子如NFATNOTCHFOX 01IRF9等调控,如果激活抗原被快速清除,PD-1水平会在响应的T细胞上降低。然而,如果抗原未被清除(如在慢性感染和癌症中),PD-1会持续高表达。

PD-L1的表达与调控

PD-L1B7系列的一种33 kDaI型跨膜糖蛋白,含有290个氨基酸。PD-L1通常由巨噬细胞、一些活化的T细胞和B细胞、树突状细胞(DCs)以及一些上皮细胞在炎症条件下表达。此外,肿瘤细胞也会表达PD-L1,作为一种适应性免疫机制以逃避抗肿瘤反应。

PD-L1的表达和调控机制非常复杂,涉及多种不同的因素以及信号通路。有研究把PD-L1的表达和调控大致分为了两类:

主要机制(非免疫驱动):包括

(1) 基因组异常:PD-L1的表达可由于基因的突变、扩增或重排导致。例如,某些肿瘤中存在的EML4-ALK融合基因可以通过MEK/ERKPI3K/Akt信号通路上调PD-L1的表达。

(2) 基于microRNA的调控:microRNA可以通过结合到PD-L1mRNA上调控其表达。例如,miR-142-5p可下调PD-L1的表达。

(3) 致癌转录因子和通路:MYCSTATsNF-κBHIF1α/2α等转录因子可以通过各种信号通路(如RAS/MEK/ERKPI3K/Akt/mTORJAK/STATsTLRs/IKKs)影响PD-L1的表达。

(4) 翻译后调控和转运:PD-L1的蛋白表达也受到翻译后修饰的调控,包括泛素化、去泛素化、磷酸化、糖基化和棕榈酰化。例如,GSK3βPD-L1相互作用并诱导其磷酸化和随后的泛素化依赖性降解。

次要机制(免疫驱动):

主要由肿瘤微环境(TME)中的免疫细胞产生的可溶性因子驱动的炎症信号激活。

例如,多种可溶性细胞因子可以诱导PD-L1的表达,IFN-γ正是之一。早期研究指出,IFN-γ可以调控多种肿瘤类型、健康组织和免疫细胞中的PD-L1表达。

PD-L1的表达调控

 

PD-1/PD-L1通路如何实现免疫逃逸的机制?

许多肿瘤细胞上调PD-L1的表达,以应对宿主的免疫压力。PD-L1可以与T细胞上的PD-1结合,传递抑制性信号,使T细胞失去杀伤活性。

PD-1PD-L1结合后,T细胞内的磷酸化事件会被抑制,影响TCRT细胞受体)的信号传导。这导致T细胞活性降低,细胞周期停滞,甚至诱导T细胞凋亡。PD-1/PD-L1通路的活化还会抑制T细胞向肿瘤部位的迁移和浸润,使得肿瘤微环境中有效的T细胞数量减少。

PD-1介导的T细胞抑制机制

具体来说,PD-L1/PD-L2PD-1结合后,会招募磷酸酶SHP-2,削弱LCK诱导的ZAP70磷酸化,并减少RAS-MEK-ERK/PI3K-Akt-mTOR通路的活性。此外,PD-1的激活会诱导BATF的表达,抑制效应基因的表达。总体而言,PD-1信号通路导致T细胞的增殖、激活、效应功能和存活受到抑制。

PD-1/PD-L1抑制剂

目前已有多种PD-1/PD-L1抑制剂被发现在癌症中起着关键作用,例如:

Pembrolizumab

pembrolizumab 是一种高度选择性的 IgG4-kappa 人源化单克隆抗体,靶向 PD-1 受体。它通过将一种高亲和力的小鼠抗人 PD-1 抗体的可变序列移植到含有稳定 S228P Fc 突变的人类 IgG4-kappa 同种型中生成。由默克公司开发,并于 2014 9 4 日获得 FDA 批准,用于治疗转移性恶性黑色素瘤,也是首个获得批准的 PD-1 抗体疗法。自首次批准以来,pembrolizumab 已获得批准用于治疗多种癌症。

Nivolumab

nivolumab 是一种人源化 IgG4 抗体,靶向PD-1。该抗体最初在小鼠中完全生产,然后移植到人类的 kappa IgG4 Fc 区域,并进行了 S228P 突变,以提高稳定性。

nivolumab 2014 12 22 日获得 FDA 批准上市。它也可以与 relatlimab 联合使用,品牌名为 Opdualag

Atezolizumab

atezolizumab 能够阻断 PD-L1 与其受体 PD-1 B7.1 之间的相互作用,从而增强 T 细胞介导的抗肿瘤免疫。atezolizumab 单药治疗已获批准用于转移性尿路上皮癌(UC)和非小细胞肺癌(NSCLC)。

Avelumab

avelumab 能够结合PD-L1,阻断其与 T 细胞和抗原呈递细胞上受体的相互作用。avelumab 2017 3 23 日首次获得 FDA 批准。同年 9 18 日和 12 18 日,分别获得了欧洲药品管理局(EMA)和加拿大卫生部的批准。它用于治疗梅克尔细胞癌、转移性尿路上皮癌或肾细胞癌。

Cemiplimab

cemiplimab 通过阻断 PD-1,旨在增强 T 细胞介导的抗肿瘤反应。于 2018 9 28 日首次获得 FDA 批准,成为首个 FDA 批准用于治疗晚期皮肤鳞状细胞癌(CSCC)的药物。随后,它也获得了用于基底细胞癌和非小细胞肺癌的批准。2022 10 月,欧洲药品管理局(EMA)药品委员会(CHMP)推荐将 cemiplimab 批准用于治疗宫颈癌。

除此之外,TargetMol还可提供多种 PD-1/PD-L1抑制剂、抗体,助力您的研究,欢迎 私信咨询~

参考资料:

Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 Pathway: Signaling, Cancer, and Beyond. Adv Exp Med Biol. 2020;1248:33-59. doi:10.1007/978-981-15-3266-5_3

Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020;10(3):727-742. Published 2020 Mar 1.

Kleffel S, Posch C, Barthel SR, et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015;162(6):1242-1256. doi:10.1016/j.cell.2015.08.052

Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800

https://en.wikipedia.org/wiki/Immune_checkpoint

https://go.drugbank.com/