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。     

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-1相关免疫调节应用的研究进展

程序性细胞死亡因子1(programmed cell death 1,PD-1)是一种共刺激分子,属于CD28家族,呈诱导性表达于活化的T细胞、B细胞和NK细胞表面,与其配体作用传递抑制性信号,发挥负向调控作用,这一信号通路在自身免疫性疾病、肿瘤发生、慢性病毒感染中具有重要的生物学意义。通过研究PD-1及其配体与临床疾病的相关性,阐明其作用机理后,利用信号调节可以达到维持自身耐受、抑制肿瘤、抗病毒和提高机体免疫应答等免疫治疗的目的。本文对PD-1及其配体的生物学功能,免疫治疗等方面的进展进行回顾。     

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。     

犬肿瘤免疫疗法的研究进展

目前,犬肿瘤疾病已成为临床常见病。手术疗法、放射疗法及化学疗法作为传统治疗手段虽然在一定程度上能够改善病犬的生存及预后,但仍不能彻底改变病犬的生存质量。因此,新的肿瘤治疗方式的引入迫在眉睫。肿瘤免疫疗法的诞生为犬类肿瘤的预防和治疗提供了契机。该文综述了犬肿瘤免疫疗法的研究进展,包括免疫检查点如程序性死亡受体1(programmed cell death 1,PD-1)/程序性死亡受体配体1(programmed cell death ligand 1,PD-L1)及细胞毒性T淋巴细胞抗原-4(cytotoxic T lymphocyte antigen-4,CTLA-4)。同时,该文评述了过继细胞疗法(adoptive cell therapy,ACT)在犬肿瘤治疗中的前景,为未来犬肿瘤治疗的研究方向提供了理论基础。     

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。     

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。     

程序性死亡配体PD-L1在肿瘤中调控机制的研究进展

肿瘤新发病例逐年增长，严重影响居民身体健康并带来了沉重的医疗负担。肿瘤免疫治疗近年来异军突起，目前肿瘤免疫治疗的主要思路是通过抑制剂或对应抗体来干扰PD-1/PD-L1轴，从而解除对T细胞免疫状态的抑制，发挥杀伤肿瘤细胞的功能，因此以PD-1/PD-L1为靶点的免疫调节对抗肿瘤有重要意义。PD-L1通常在各种恶性肿瘤中表达上调，最新证据表明存在多种潜在机制或信号通路调控PD-L1表达，基于此开发特异的小分子抑制剂在抑制关键致癌信号通路的同时，还能抑制PD-L1表达，从而实现免疫检查点抑制剂联合靶向药物疗法的突破，发挥协同抗肿瘤效应。本文就癌症中PD-L1在基因突变、表观遗传修饰、转录和翻译后修饰水平的调控机制展开论述，为进一步开展联合靶向疗法提供理论基础。     

CTLA-4和PD-1信号通路在实体瘤治疗中的研究进展

细胞毒性T淋巴细胞相关抗原4(cytotoxic T-lymphocyte-associated antigen 4,CTLA-4)和程序性死亡受体1(programmed death 1,PD-1)免疫检查点在T细胞免疫反应中起负性调节作用。通过对这些靶点的抑制,可增强对免疫系统的激活,为黑色素瘤、非小细胞肺癌等提供新的免疫治疗途径。CTLA-4和PD-1信号通路在免疫反应及抗肿瘤中机制有所不同,针对这两条信号通路的免疫检查点抑制剂也具有不同的效应。现将综述CTLA-4和PD-1信号通路的作用机制及相应靶点阻断剂在实体肿瘤免疫治疗中的应用及研究进展。     

不同检测策略在预测非小细胞肺癌的PD1/PD-L1抑制剂临床疗效中的应用

近10年来,程序性死亡因子1(programmed death-1,PD-1)及其配体(programmed death ligand-1,PD-L1)的抑制剂在非小细胞肺癌(non-small cell lung cancer,NSCLC)的临床治疗中取得了重大突破,有望改变晚期NSCLC的治疗方式。然而,PD-1/PD-L1抑制剂在对NSCLC的治疗中需要借助有效的生物标志物以寻找受益人群(约20%～40%)。目前,临床上主要的判断标准是PD-L1的表达水平。本文综述了近年来在NSCLC中,与预测PD-1/PD-L1抑制剂疗效的PD-L1表达相关的检测方法,包括免疫组化、基于DNA/RNA水平检测、可溶性PD-L1的检测、正电子发射断层显像(positron emission tomography,PET)技术、多重免疫组化技术、流式细胞术和液体活检技术等,着重探讨了不同检测策略在评价PD-L1表达上的最新进展及应用前景,从而推动其在NSCLC免疫治疗中的临床应用。     

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     

Is it true that gut microbiota is considered as panacea in cancer therapy?

Recent studies demonstrated that a combination of the gut microbiome has the vital effect on the efficacy of anticancer immune therapies. Regulatory effects of microbiota have been shown in different types of cancer therapies such as chemotherapy and immunotherapy. Immune-checkpoint-blocked therapies are the recent efficient cancer immunotherapy strategies. The target of immune-checkpoint blocking is cytotoxic T lymphocyte protein-4 (CTLA-4) or blockade of programmed death-1 (PD-1) protein and its ligand programmed death ligand 1 (PD-L1) that they have been considered as cancer immunotherapy in recent years. In the latest studies, it have been demonstrated that several gut bacteria such as Akkermansia muciniphila, Bifidobacterium spp., Faecalibacterium spp., and Bacteroides fragilis have the regulatory effects on PD-1, PD-L1, and CTLA-4 blocked anticancer therapy outcome.     

Increased Level of Myeloid-Derived Suppressor Cells,Programmed Death Receptor Ligand 1/Programmed Death Receptor 1, and Soluble CD25 in Sokal High Risk Chronic Myeloid Leukemia

Immunotherapy (eg interferon α) in combination with tyrosine kinase inhibitors is currently in clinical trials for treatment of chronic myeloid leukemia (CML). Cancer patients commonly have problems with so called immune escape mechanisms that may hamper immunotherapy. Hence, to study the function of the immune system in CML is of interest. In the present paper we have identified immune escape mechanisms in CML with focus on those that directly hamper T cells since these cells are important to control tumor progression. CML patient samples were investigated for the presence of myeloid-derived suppressor cells (MDSCs), expression of programmed death receptor ligand 1/programmed death receptor 1 (PD-L1/PD-1), arginase 1 and soluble CD25. MDSC levels were increased in samples from Sokal high risk patients (p<0,05) and the cells were present on both CD34 negative and CD34 positive cell populations. Furthermore, expression of the MDSC-associated molecule arginase 1, known to inhibit T cells, was increased in the patients (p = 0,0079). Myeloid cells upregulated PD-L1 (p<0,05) and the receptor PD-1 was present on T cells. However, PD-L1 blockade did not increase T cell proliferation but upregulated IL-2 secretion. Finally, soluble CD25 was increased in high risk patients (p<0,0001). In conclusion T cells in CML patients may be under the control of different immune escape mechanisms that could hamper the use of immunotherapy in these patients. These escape mechanisms should be monitored in trials to understand their importance and how to overcome the immune suppression.     

Implication of the hepatokine,fibrinogen-like protein 1 in liver diseases,metabolic disorders and cancer: The need to harness its full potential

Fibrinogen-like protein 1 (FGL1) is a novel hepatokine that forms part of the fibrinogen superfamily. It is predominantly expressed in the liver under normal physiological conditions. When the liver is injured by external factors, such as chemical drugs and radiation, FGL1 acts as a protective factor to promote the growth of regenerated cells. However, elevated hepatic FGL1 under high fat conditions can cause lipid accumulation and inflammation, which in turn trigger the development of non-alcoholic fatty liver disease, diabetes, and obesity. FGL1 is also involved in the regulation of insulin resistance in adipose tissues and skeletal muscles as a means of communication between the liver and other tissues. In addition, the abnormally changed FGL1 levels in the plasma of cancer patients make it a potential predictor of cancer incidence in clinical practice. FGL1 was recently identified as a major functional ligand of the immune inhibitory receptor, lymphocyte-activation gene 3 (LAG3), thus making it a promising target for cancer immunotherapy except for the classical programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) axis. Despite the potential of FGL1 as a new cancer biomarker and therapeutic target, there are few related studies and much of what has been reported are superficial and lack depth and particularity. Therefore, elucidating the role and underlying mechanisms of FGL1 could be crucial for the development of promising diagnostic and therapeutic strategies for related diseases. Here, we provide a comprehensive review of the cellular mechanisms and clinical prospects of FGL1 in the prevention and treatment of liver diseases, metabolic disorders and cancer, and proffer suggestions for future studies.     

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.     

Programmed death ligand-1 over-expression correlates with malignancy and contributes to immune regulation in ovarian cancer

The programmed death-1 (PD-1) pathway is important in the maintenance of peripheral tolerance and homeostasis through suppression of T cell receptor signaling. As such, it is employed by many tumors as a means of immune escape. We have investigated the role of this pathway in human ovarian cancer (OC) to assess its potential role as a diagnostic and/or prognostic marker and therapeutic target, following recent clinical trial success of antibody therapy directed at this pathway. We show programmed death ligand-1 (PD-L1) expression on monocytes in the ascites and blood of patients with malignant OC is strikingly higher than those with benign/borderline disease, with no overlap in the values between these groups. We characterize the regulation of this molecule and show a role of IL-10 present in ascitic fluid. Flow cytometric analysis of T cells present in the ascites and blood showed a correlation of PD-1 expression with malignant tumors versus benign/borderline, in a similar manner to PD-L1 expression on monocytes. Finally, we demonstrate functional links between PD-L1 expression on monocytes and OC tumor cells with suppression of T cell responses. Overall, we present data based on samples obtained from women with ovarian cancer, suggesting the PD-1 pathway may be used as a reliable diagnostic marker in OC, as well as a viable target for use with PD-1/PD-L1-directed antibody immunotherapy.     

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.