PD-1/PD-L1信号通路及相关抗体在宫颈癌免疫治疗中的应用

程序性死亡蛋白1(PD-1)是T细胞上主要存在的一种抑制性受体,其与程序性死亡配体1(PD-L1)相互作用,可抑制T细胞增殖、活化和细胞因子的分泌。在肿瘤进展中,PD-1/PD-L1信号通路能够抑制T细胞的免疫反应而促进肿瘤免疫逃逸的发生。PD-1及PD-L1作为一种免疫应答的关键调控蛋白,与宫颈癌的发生发展及预后密切相关,PD-1及PD-L1抗体的深入研究将为治疗宫颈癌提供新的分子靶标。本文就PD-1/PD-L1生物学结构功能、在肿瘤的发生发展中的作用及其抗体在宫颈癌免疫治疗中的应用前景作一简要综述。     

PD-1/PD-L1抗体在肿瘤临床治疗中的应用

PD-1是主要表达在活化T细胞上的免疫抑制性受体,与表达在肿瘤细胞表面的配体PD-L1结合,通过降低T细胞的免疫应答,使肿瘤免疫逃逸。靶向PD-1/PD-L1这一信号通路的单克隆抗体类药物的研发是当前抗肿瘤治疗领域的研究热点。目前,已有多项临床研究提示,PD-1及PD-L1抗体药物治疗肿瘤的疗效显著且不良反应较小,有望改善部分晚期肿瘤患者的预后。     

PD-L1表达及其调控在肿瘤治疗中作用的研究进展

程序性死亡蛋白1(programmed cell death 1, PD-1)及其配体PD-L1(programmed death 1 ligand 1)是重要的免疫检查点，二者相互作用可负性调节效应T细胞活化与增殖，也是肿瘤细胞逃避免疫监视的重要途径。阻断PD-1与PD-L1的结合，可以解除肿瘤细胞或抗原提呈细胞对T细胞的抑制，恢复其对肿瘤细胞的识别和杀伤能力。然而，PD-L1的表达受到复杂的调控且在不同的肿瘤中呈现出差异，其主要发生在遗传、转录和转录后水平。本综述介绍PD-L1表达的调控过程及其在肿瘤免疫治疗中的作用，结合这些调控机制实现对不同特征肿瘤进行精准免疫治疗是下一步研究的重点，在肿瘤治疗中具有重要意义。     

PD-L1降解途径与肿瘤免疫治疗

程序性死亡受体配体1 (programmed death ligand 1, PD-L1)是肿瘤免疫检查点阻断治疗中的重要靶点,其在多种细胞中均有表达。肿瘤细胞可通过高表达PD-L1来增强程序性死亡受体1 (programmed death 1, PD-1)抑制信号,从而促进肿瘤免疫逃逸。近年来,以抗PD-1/PD-L1抗体为代表的肿瘤免疫治疗给癌症治疗带来了革命性的变化。然而,肿瘤免疫治疗仅能对部分患者产生持久的疗效,多数患者对肿瘤免疫治疗的应答短暂或没有应答。研究发现, PD-L1的降解对肿瘤免疫治疗应答至关重要。本文综述了PD-L1的溶酶体降解途径、蛋白酶体降解途径及PD-L1降解与肿瘤免疫治疗的相互作用,旨在为进一步增强肿瘤免疫治疗的应答率和应答范围提供研究思路。     

肾透明细胞癌中免疫检查点相关的免疫逃逸机制的研究进展

摘要：近年来,免疫治疗在晚期肾透明细胞癌的治疗中异军突起,使人们对于肾癌治疗有了全新的认识。肿瘤免疫治疗药物是通过抑制免疫检查点从而抑制肿瘤细胞免疫逃逸,使免疫细胞可以杀伤肿瘤细胞来发挥治疗作用。因此,了解肾透明细胞癌中免疫检查点相关免疫逃逸机制对于制定有效的治疗策略以及开发新的免疫治疗药物至关重要。本文对目前肾透明细胞癌中主要的免疫检查点（PD-1/PD-L1、CTLA-4、B7-H4、LAG-3、TIM-3和HLA-G）相关的免疫逃逸机制进行综述。     

PD-L1表达调控通路-治疗肿瘤潜在的新途径

癌细胞表面能表达多种免疫抑制蛋白,程序性死亡分子受体1配体(programmed death ligand-1,PD-L1)是关键蛋白之一,可与免疫细胞(如T细胞、B细胞、树突状细胞和自然杀伤性T细胞)表面的程序性死亡受体-1(programmed death ligand,PD-1)结合,激活PD-1的免疫抑制作用,通过RAS/Raf/MEK/ERK、磷脂酶C-γ(phospholipase C-γ,PLC-γ)、磷脂酰肌醇-3-激酶-蛋白激酶B(PI3K-AKT)等通路下调机体免疫细胞功能,协助癌细胞进行免疫逃逸。故近年来应用免疫检查点PD-1、PD-L1抑制剂成为治疗恶性肿瘤的新手段。研究表明,PD-L1的表达受多种信号通路、相关蛋白和转录因子的调控,故本文就PD-L1的表达调控进行综述,寻求PD-L1表达调控通路能否作为抗肿瘤治疗新的靶点。     

白细胞介素-8与肿瘤免疫逃逸

IL-8是趋化因子CXC家族的一员,是一种多细胞来源的细胞因子,在细胞的多种炎症反应中起调节作用,并且在自身免疫性疾病中也发挥重要作用。IL-8通过与细胞膜上的CXC趋化因子受体CXCR1和CXCR2相互作用,激活偶联的G蛋白,由G蛋白进一步激活PLC、AC、PLD、PI3K、JAK2及Ras等信号分子,从而调控基因表达、细胞增殖和分化、细胞代谢、细胞运动及血管生成等多种细胞生命过程。IL-8在多种恶性肿瘤细胞中表达量升高,其高表达与肿瘤细胞增殖、迁移、侵袭、血管生成及上皮间充质转化有密切联系。肿瘤免疫逃逸是肿瘤细胞产生和转移过程中的主要特征之一,肿瘤细胞可以通过多种机制使得人体免疫系统无法对其进行正常的识别和攻击,从而导致肿瘤细胞在体内存活,并且不断增殖和转移,而肿瘤细胞、免疫细胞以及肿瘤微环境中其他相关组分均可以促进肿瘤免疫逃逸。IL-8作为一种炎性趋化因子,已被证明在肿瘤免疫逃逸中具有重要作用,其可通过诱导肿瘤细胞PD-L1表达、抑制肿瘤细胞凋亡、促进肿瘤细胞EMT进程、促进肿瘤微环境血管生成、招募免疫抑制性细胞等五个方面介导肿瘤免疫逃逸。IL-8中和抗体和CXCR1/2拮抗剂在抗肿瘤治疗方面已经显示出较好的治疗效果。     

免疫检查点蛋白质PD-1的信号转导通路与肿瘤免疫治疗

程序性死亡受体-1(programmed death-1,PD-1)是B7-CD28(B7 family-cluster of differentiation28)家族最新发现的成员,其在肿瘤免疫逃逸和免疫耐受中发挥着重要的作用。PD-1作为抑制性受体,在T细胞的信号转导中发挥着关键性作用,能够通过阻断与PD-1/程序性死亡受体-1配体-1(programmed death-1 ligand-1,PD-L1)信号通路,能够促进T淋巴细胞的增殖和分化,从而激活抗肿瘤免疫反应。而作为PD-1配体的PD-L2,除了在肿瘤免疫中发挥作用外,还在哮喘、过敏性反应等方面起着重要作用。该文就PD-1、PD-Ls与PD-1/PD-Ls信号通路以及PD-1抗体在肿瘤免疫治疗中的应用作一综述。     

PD-1胞外段cDNA在真核细胞的表达与其功能鉴定

PD-L/PD-1是参与肿瘤免疫逃避的一条抑制性信号途径。为了用可溶性的PD 1受体阻断PD-L/PD-1的相互作用 ,将小鼠PD-1胞外段 (aa1-aa167)作为独立可溶性分子进行了真核表达 ,并对其功能进行鉴定。构建了编码小鼠PD-1胞外段cDNA(sPD 1)的真核质粒表达载体pPD-1A和编码sPD-1-GFP重组蛋白的真核质粒表达载体pPD-1B ;细胞转染实验表明其表达产物主要是分泌到细胞外的可溶性产物 (sPD-1) ,流式细胞仪检测表明sPD-1可有效结合PD-1配体 ;肿瘤细胞杀伤实验表明 ,sPD-1作用于肿瘤细胞或在脾淋巴细胞激活过程中作用于淋巴细胞 ,均可增强Hsp70-H22抗原肽复合物激活的脾淋巴细胞杀伤肿瘤细胞的作用。sPD-1真核表达载体的构建为在肿瘤局部表达抑制性共刺激分子的可溶性受体 ,拮抗肿瘤微环境中负调节因素对T细胞的抑制作用 ,增强机体的抗肿瘤能力 ,提供了一种新的肿瘤基因治疗手段     

PD-1及其配体PD-L在HIV感染中的作用

共刺激信号不仅可以协助激活T细胞,而且可以通过负性共刺激信号下调免疫反应,从而精确地调节应答的程度和持续时间。以PD-1/PD-L为代表的负性共刺激途径,在免疫学的试验研究和临床免疫治疗中均有重要意义,近年来该途径被认为与移植排斥反应、自身免疫性疾病、肿瘤免疫逃逸,尤其是慢性病毒感染如艾滋病等疾病密切相关。本文主要介绍PD-1及其配体PD-L的结构、表达特性及其在HIV感染中的作用,探讨其在艾滋病病情发展中的作用机制和治疗方面的应用前景。     

The role of exosomal PD-L1 in tumor immunotherapy

Exosomes are bioactive lipid bilayer vesicles released by most cells to mediate intercellular signal communication. Tumor cells release exosomes transmitting signals cell-to-cell and between cells and organs, which will promote tumor angiogenesis, regulate tumor stromal response, immune response, and enhance tumor cells resistance, while exosomes-derived from immune cells in tumor microenvironment play a key role in inhibiting tumor growth and killing tumor cells. Programmed cell death protein 1 (PD-1) combined with Programmed cell death protein ligand 1(PD-L1) can inhibit the activation of T cells, for tumor cells achieve immune escape by overexpressing PD-L1 and binding PD-1 on T cells. The use of anti-PD-1 / PD-L1 antibodies prevents their binding to a certain extent and partially restores T cell's activity. This article mainly discusses the role of exosomal PD-L1 in tumor progression and therapeutic efficacy after application of clinical antibodies, as well as the relation between different reactivity and immunity set points in cancer patients of different races, with different types and at different stages. Besides, we propose that exosomal PD-L1 may become targets for anti-PD-1 / PD-L1 antibody therapy, biomarkers for liquid biopsy, and drug carriers.     

免疫检查点程序性细胞死亡蛋白配体-1翻译后修饰及其在免疫治疗中的应用前景

免疫检查点程序性细胞死亡蛋白配体-1(programmed cell death 1 ligand 1,PD-L1)是一种主要表达于肿瘤细胞表面的免疫抑制性分子,其可与T淋巴细胞表面的程序性细胞死亡蛋白-1(programmed cell death protein 1,PD-1)结合,抑制T淋巴细胞的激活,发挥免疫抑...     

PD-1/PD-L1 immune checkpoint: Potential target for cancer therapy

Recent studies show that cancer cells are sometimes able to evade the host immunity in the tumor microenvironment. Cancer cells can express high levels of immune inhibitory signaling proteins. One of the most critical checkpoint pathways in this system is a tumor-induced immune suppression (immune checkpoint) mediated by the programmed cell death protein 1 (PD-1) and its ligand, programmed death ligand 1 (PD-L1). PD-1 is highly expressed by activated T cells, B cells, dendritic cells, and natural killer cells, whereas PD-L1 is expressed on several types of tumor cells. Many studies have shown that blocking the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity. In this review, we highlight a brief overview of the molecular and biochemical events that are regulated by the PD-1 and PD-L1 interaction in various cancers.     

Deubiquitinating enzyme OTUB1 promotes cancer cell immunosuppression via preventing ER-associated degradation of immune checkpoint protein PD-L1

Upregulation of programmed death ligand 1 (PD-L1) helps tumor cells escape from immune surveillance, and therapeutic antibodies targeting PD-1/PD-L1 have shown better patient outcomes only in several types of malignancies. Recent studies suggest that the clinical efficacy of anti-PD-1/PD-L1 treatments is associated with PD-L1 levels; however, the underlying mechanism of high PD-L1 protein levels in cancers is not well defined. Here, we report that the deubiquitinase OTUB1 positively regulates PD-L1 stability and mediates cancer immune responses through the PD-1/PD-L1 axis. Mechanistically, we demonstrate that OTUB1 interacts with and removes K48-linked ubiquitin chains from the PD-L1 intracellular domain in a manner dependent on its deubiquitinase activity to hinder the degradation of PD-L1 through the ERAD pathway. Functionally, depletion of OTUB1 markedly decreases PD-L1 abundance, reduces PD-1 protein binding to the tumor cell surface, and causes increased tumor cell sensitivity to human peripheral blood mononuclear cells (PBMCs)-mediated cytotoxicity. Meanwhile, OTUB1 ablation-induced PD-L1 destabilization facilitates more CD8⁺ T cells infiltration and increases the level of IFN-γ in serum to enhance antitumor immunity in mice, and the tumor growth suppression by OTUB1 silencing could be reversed by PD-L1 overexpression. Furthermore, we observe a significant correlation between PD-L1 abundance and OTUB1 expression in human breast carcinoma. Our study reveals OTUB1 as a deubiquitinating enzyme that influences cancer immunosuppression via regulation of PD-L1 stability and may be a potential therapeutic target for cancer immunotherapy.Subject terms: Proteins, Immune evasion     

Programmed cell death-ligand 2: A neglected but important target in the immune response to cancer?

Programmed cell death-ligand 2 (PD-L2) is one of the two ligands of the programmed cell death-1 (PD-1) receptor, an inhibitory protein mainly expressed on activated immune cells that is targeted in the clinic, with successful and remarkable results. The PD-1/PD-Ls axis was shown to be one of the most relevant immunosuppressive pathways in the immune microenvironment, and blocking this interaction gave rise to an impressive clinical benefit in a broad variety of solid and hematological malignancies. Although PD-L2 has been historically considered a minor ligand, it binds to PD-1 with a two- to six-fold higher affinity as compared to PD-L1. PD-L2 can be expressed by immune, stromal, or tumor cells. The aims of this narrative review are to summarize PD-L2 biology in the physiological responses of the immune system and its role, expression, and clinical significance in cancer.     

RNA interference targeting programmed death receptor-1 improves immune functions of tumor-specific T cells

Adoptive cell transfer (ACT), either using rapidly expanded tumor infiltrating lymphocytes or T-cell receptor transduced peripheral blood lymphocytes, can be considered one of the most promising approaches in cancer immunotherapy. ACT results in the repopulation of the host with high frequencies of tumor-specific T cells; however, optimal function of these cells within the tumor micro-environment is required to reach long-term tumor clearance. We and others have shown that ongoing anti-tumor immune responses can be impaired by the expression of ligands, such as PD-L1 (B7-H1) on tumor cells. Such inhibitory molecules can affect T cells at the effector phase via their receptor PD-1. PD-L1/PD-1 interaction has indeed been shown crucial in inducing T-cell anergy and maintaining peripheral tolerance. In order to maximize anti-tumor responses, antibodies that target the PD-1/PD-L1 axis are currently in phase I/II trials. Alternatively, a more refined approach could be the selective targeting of PD-1 in tumor-specific T cells to obtain long-term resistance against PD-1-mediated inhibition. We addressed whether this goal could be achieved by means of retroviral siRNA delivery. Effective siRNA sequences resulting in the reduction of surface PD-1 expression led to improved murine as well as human T-cell immune functions in response to PD-L1 expressing melanoma cells. These data suggest that blockade of PD-1-mediated T-cell inhibition through siRNA forms a promising approach to achieve long-lasting enhancement of tumor-specific T-cell function in adoptive T-cell therapy protocols.     

New insights into the important roles of tumor cell-intrinsic PD-1

PD-1 (Programmed cell death protein-1) is mainly expressed in various immune cells, while its ligands PD-L1/PD-L2 (Programmed death ligand-1/Programmed death ligand-2) are mostly expressed in tumor cells. Generally, the binding of PD-L1/PD-L2 and PD-1 could lead to the tumor immune evasion. However, some recent studies showed that PD-1 could also be expressed in tumor cells and could activate mTOR (Mammalian Target of Rapamycin) or Hippo signaling pathway, therefore facilitating tumor proliferation independent of the immune system. While there was evidence that tumor cell-intrinsic PD-1 inhibited the activation of AKT and ERK1/2 pathways, thereby inhibiting tumor cell growth. Based on TCGA and CCLE database, we found that PD-1 was expressed in a variety of tumors and was associated with patient''s prognosis. Besides, we found that PD-1 may be involved in many carcinogenic signaling pathway on the basis of PD-1 gene enrichment analysis of cancer tissues and cancer cells. Our understanding of the tumor cell-intrinsic PD-1 function is still limited. This review is aimed at elaborating the potential effects of tumor cell-intrinsic PD-1 on carcinogenesis, providing a novel insight into the effects of anti-PD-1/PD-L1 immunotherapy, and helping to open a major epoch of combination therapy.     

B7-DC-Ig Enhances Vaccine Effect by a Novel Mechanism Dependent on PD-1 Expression Level on T Cell Subsets

Programmed death receptor 1 (PD-1) is an important signaling molecule often involved in tumor-mediated suppression of activated immune cells. Binding of this receptor to its ligands, B7-H1 (PD-L1) and B7-DC (PD-L2), attenuates T cell activation, reduces IL-2 and IFN-γ secretion, decreases proliferation and cytotoxicity, and induces apoptosis. B7-DC-Ig is a recombinant protein that binds and targets PD-1. It is composed of an extracellular domain of murine B7-DC fused to the Fc portion of murine IgG2a. In this study, we demonstrate that B7-DC-Ig can enhance the therapeutic efficacy of vaccine when combined with cyclophosphamide. We show that this combination significantly enhances Ag-specific immune responses and leads to complete eradication of established tumors in 60% of mice and that this effect is CD8 dependent. We identified a novel mechanism by which B7-DC-Ig exerts its therapeutic effect that is distinctly different from direct blocking of the PD-L1-PD-1 interaction. In this study, we demonstrate that there are significant differences between levels and timing of surface PD-1 expression on different T cell subsets. We found that these differences play critical roles in anti-tumor immune effect exhibited by B7-DC-Ig through inhibiting proliferation of PD-1(high) CD4 T cells, leading to a significant decrease in the level of these cells, which are enriched for regulatory T cells, within the tumor. In addition, it also leads to a decrease in PD-1(high) CD8 T cells, tipping the balance toward nonexhausted functional PD-1(low) CD8 T cells. We believe that the PD-1 expression level on T cells is a crucial factor that needs to be considered when designing PD-1-targeting immune therapies.