纳米刀消融联合程序性死亡蛋白-1/程序性死亡蛋白配体-1治疗胰腺癌及其免疫学机制研究进展

胰腺癌特殊的肿瘤微环境不利于免疫治疗,而纳米刀消融可在一定程度上逆转免疫抑制,使其成为目前唯一适用于胰腺癌的消融治疗方法。动物研究结果证实,纳米刀消融联合程序性死亡蛋白-1（PD-1）/程序性死亡蛋白配体-1（PD-L1）治疗胰腺癌可延长患者生存时间。本文对纳米刀消融联合PD-1/PD-L1治疗胰腺癌及其免疫学机制研究进展进行综述。     

抗PD-1/PD-L1抗体在肿瘤治疗中的研究

正PD-1及其配体PD-L1在维持外周免疫耐受中起着至关重要的作用。肿瘤细胞可通过PD-1/PD-L1轴,逃避T细胞介导的肿瘤特异性免疫[1]。众多临床试验表明,基于上述机制开发的抗PD-1/PD-L1抗体,是一种广谱、有效、作用持久且相对安全的抗肿瘤治疗方式[2]。自2012年抗PD-1/PD-L1抗体首次临床试验结果发表以来,已研究160余种阻断PD-     

PD-1/PD-L1抑制剂在胃癌中的研究现状

目的阐述程序性死亡受体蛋白-1(PD-1)及其配体-1(PD-L1)抑制剂在胃癌中的研究现状,了解PD-1/PD-L1抑制剂存在的关键问题,为以后的研究提供理论基础。方法复习经典及最新有关免疫治疗,尤其是PD-1/PD-L1抑制剂的文献并综述之。结果PD-1/PD-L1抑制剂是目前肿瘤免疫治疗研究中的热点,派姆单抗及纳武单抗在临床免疫抑制剂治疗研究中较常用,继在血液系统恶性肿瘤和恶性黑色素瘤中展示出良好疗效后,二者在胃癌临床研究中也取得了较大成功。在一些临床研究中,PD-1/PD-L1抑制剂治疗患者相较常规化疗患者总生存期延长,尤其是在PD-1阳性患者中的疗效更为显著,但是其研究仍存在无法精确预测受益人群、肿瘤免疫超进展等亟待解决的问题,可喜的是,目前肿瘤免疫基础研究成果日益增多,为解决这些问题在理论方面提供了有力支撑。结论PD-1/PD-L1抑制剂等肿瘤免疫抑制剂疗法为胃癌患者的治疗提供了新思路,尽管其在临床研究中仍存在较多问题,但随着研究的进一步深入,PD-1/PD-L1抑制剂必将成为晚期胃癌患者治疗的利器之一。     

程序性死亡-1及其配体信号通路在移植免疫中的作用

程序性死亡-1(PD-1)为负性调控共刺激分子,系T淋巴细胞和B淋巴细胞表面受体,属于免疫球蛋白超家族Ⅰ型跨膜糖蛋白,在T、B淋巴细胞抗原受体激发后呈诱导性表达.PD-1与其2个配体PD-L1和PD-L2结合,在免疫应答中起着负性调控作用.目前,人们愈加关注PD-1/PD-L信号通路与临床疾病的关系,如移植后排斥反应、哮喘、1型糖尿病等~([1]).本文对PD-1/PD-L信号通路在移植免疫中的作用进行如下综述.     

程序性死亡受体1及其配体抑制剂治疗骨肉瘤的研究进展

新辅助化疗结合手术治疗使骨肉瘤患者的5年生存率超过50%,但是,合并复发或转移的骨肉瘤患者其预后仍较差。免疫检查点抑制剂是近年肿瘤领域的研究热点,其中针对程序性死亡受体1及其配体(PD-1/PD-L1)的免疫治疗已在多种人类肿瘤治疗中取得较好疗效。随着肿瘤免疫研究的不断深入,包括PD-1/PD-L1抑制剂在内的免疫治疗在骨肉瘤综合治疗中已发挥越来越重要的作用。该文对PD-1/PD-L1抑制剂治疗骨肉瘤的研究现状进行综述,希望为骨肉瘤的免疫治疗研究提供参考。     

PD-1/PD-L1抑制剂治疗进展期胃癌的现状与进展

目的 探讨以程序性死亡受体1(programmed cell death 1,PD-1)/程序性死亡受体配体1(programmed cell death ligand-1,PD-L1)抑制剂为代表的免疫治疗药物在进展期胃癌中的临床价值。方法 检索有关PD-1/PD-L1抑制剂在进展期胃癌中应用的最新文献并进行综述。结果 PD-1/PD-L1抑制剂在进展期胃癌的治疗、生物标志物及耐药情况方面均有相应的临床试验研究，其单药或它联合化学药物或（和）靶向药物治疗进展期胃癌或胃食管交界癌，有部分患者表现出较好的疗效，从PD-1/PD-L1抑制剂获益的患者可能是具有特定分子特征的群体，但在治疗过程中耐药性的出现影响了其疗效。结论 从本综述了解的进展看，PD-1/PD-L1抑制剂治疗能使部分进展期胃癌患者获益，但仍需寻找更多用于可预测疗效的生物标志物以优化用药方案，同时还需深入研究其耐药机制以解决耐药问题。     

PD-1/PD-L1信号通路在不同组织来源间充质干细胞中免疫调节作用的研究进展

间充质干细胞(MSCs)是一类具有自我更新、多向分化、免疫调节功能的干细胞,能够从骨髓、脂肪、脐血等组织中分离得到。程序性死亡分子1(PD-1)/程序性死亡分子1配体(PD-L1)信号通路在免疫反应的负性调控和维持外周免疫耐受中发挥着重要作用。近年来,PD-1/PD-L1信号通路在MSCs中的作用逐渐受到重视。本文就PD-1/PD-L1通路在不同组织来源MSCs中免疫调节作用的研究现状进行综述。     

胰腺导管腺癌的免疫治疗研究进展

胰腺导管腺癌（PDAC）是常见的消化系统恶性肿瘤,恶性程度高,容易发生转移,手术切除率低。近年来,以程序性细胞死亡蛋白1/程序性死亡配体1（PD-1/PD-L1）抗体为代表的免疫检查点抑制剂在肿瘤的免疫治疗中取得了重大进展。然而,由于PDAC独特的肿瘤微环境及低免疫原性,PDAC的免疫治疗并不尽如人意。结合PDAC的微环境特点,笔者介绍免疫检查点抑制剂、过继细胞免疫以及肿瘤疫苗等在PDAC治疗中的进展和潜在的应用前景。     

微小RNA-155在M1型、M2型巨噬细胞及肿瘤相关巨噬细胞中的表达差异

目的探讨微小RNA-155(mi R-155)在巨噬细胞M1型、M2型及肿瘤相关巨噬细胞(TAMs)中的表达差异。方法将单核细胞系(THP-1)细胞诱导为巨噬细胞M1型、M2型及TAMs,应用流式细胞仪检测表型后,采用荧光染料法实时定量PCR(SYBR Green q RT-PCR)方法分别检测THP-1、巨噬细胞M1型、M2型及TAMs中mi R-155的表达情况。结果 M1型巨噬细胞中mi R-155的表达量为6.580±0.637,M2型巨噬细胞中的表达量为1.83±0.337,TAMs细胞中的表达量为1.60±0.233。单因素方差分析结果显示组间差异有统计学意义(F=1.238,P=0.000)。其中M2型(P=0.000)及TAMs(P=0.000)巨噬细胞中mi R-155的表达量显著低于M1型;TAMs的表型与巨噬细胞M2型的表型相似,TAMs与M2型巨噬细胞中mi R-155的表达差异无统计学意义(P=0.546)。结论 mi R-155在巨噬细胞M1型、M2型中的差异性表达可能与其分化和/或细胞功能相关。TAMs的表型特征可能与巨噬细胞M2型类似,同时可能具有与巨噬细胞M2型相同的细胞功能。     

急性排斥反应时移植肾组织中程序性死亡配体-1及其受体的表达

目的探讨急性排斥反应时移植肾组织中程序性死亡配体-1(PD-L1)及程序性死亡-1(PD-1)的表达及其与肾小管间质病理损害程度的关系。方法当肾移植患者发生急性排斥反应并经病理检查确认时,采取移植肾组织,以免疫组化和原位杂交染色法,观察肾组织中PD-L1和PD-1的表达,分析PD-L1阳性强度与肾小管-间质PD-1阳性细胞数、肾小管间质病理损害程度的关系。以正常肾组织为对照。结果急性排斥反应时,移植肾组织中的PD-L1及PD-1的表达较正常组织增多、增强(P<0.01);肾小管PD-L1阳性强度与肾间质PD-1阳性细胞数呈正相关,与肾小管间质病理损害程度呈负相关。结论急性排斥反应时,PD-L1及PD-1的表达增强,它们可能在肾小管间质病理损害中起重要作用。     

Porcine PD-L1: cloning, characterization, and implications during xenotransplantation

BACKGROUND: Effective intervention achieved by manipulating cell-mediated xenogeneic immune responses would critically increase the clinical feasibility of xenotransplantation as immediate hyperacute rejections become controllable through genetic modulations of donor organs. Endogenous negative regulatory signals like the programmed death 1 (PD-1)-programmed death ligand 1 (PD-L1) system are candidate targets for the control of cell-mediated xenogeneic immune response. METHODS: A porcine PD-L1 molecule was cloned using RACE (rapid amplification of cDNA ends) technology based on the human PD-L1 sequence. The functional effects of cloned porcine PD-L1 were tested on human CD4(+) T cell activation using porcine PD-L1-transfected bystander cells. Cellular proliferation was monitored by [3H] thymidine incorporation, and human T cell apoptosis was measured by flow cytometry. RESULTS: Porcine PD-L1 (GenBank accession number AY837780) was found to have 73.8% sequence homology with human PD-L1 and to contain two immunoglobulin domains in its extracellular region. Moreover, porcine PD-L1 expressed on Chinese hamster ovary (CHO) cells inhibited human CD4(+) T cell proliferation stimulated with anti-CD3 only or anti-CD3 plus anti-CD28. Percentages of apoptotic activated human T cells increased by over 30% in the presence of porcine PD-L1/CHO cells, and the addition of recombinant human PD-1-Fc fusion proteins during human T cell activation reversed the inhibitory effects of porcine PD-L1. CONCLUSIONS: Cloned porcine PD-L1 showed high sequence homology with human PD-L1 and a similar molecular structure. Moreover, porcine PD-L1 inhibited human CD4(+) T cell activation in human PD-1-dependent manner, and this involved activated T cell apoptosis. The authors suggest that PD-1-PD-L1 might play an important endogenous immune regulatory role during xenogeneic transplantation, and that the effective application of this system would improve transplanted xenogeneic organ survival.     

Research progress regarding programmed cell death 1/programmed cell death ligand 1 inhibitors combined with targeted therapy for treating hepatocellular carcinoma

In recent years, a number of targeted therapeutic agents have achieved success in phase III trials in patients with advanced hepatocellular carcinoma (HCC), including sorafenib, lenvatinib, and regorafenib. Immunotherapy is considered to be an effective treatment for advanced HCC. Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are important antitumor immunotherapy agents that represent breakthroughs in the treatment of advanced HCC. However, treating advanced HCC is still a great challenge, and the need for new treatments remains urgent. This review briefly summarizes the research progress in the use of PD-1/PD-L1 inhibitors combined with targeted therapy for treating HCC.     

Protective role of programmed death 1 ligand 1 (PD-L1)in nonobese diabetic mice: the paradox in transgenic models

OBJECTIVE—Coinhibitory signals mediated via programmed death 1 (PD-1) receptor play a critical role in downregulating immune responses and in maintaining peripheral tolerance. Programmed death 1 ligand 1 (PD-L1), the interacting ligand for PD-1, widely expressed in many cell types, acts as a tissue-specific negative regulator of pathogenic T-cell responses. We investigated the protective potential of PD-L1 on autoimmune diabetes by transgenically overexpressing PD-L1 in pancreatic β-cells in nonobese diabetic (NOD) mice.RESEARCH DESIGN AND METHODS—We established an insulin promoter–driven murine PD-L1 transgenic NOD mouse model to directly evaluate the protective effect of an organ-specific PD-L1 transgene against autoimmune diabetes. Transgene expression, insulitis, and diabetic incidence were characterized in these transgenic NOD mice. Lymphocyte development, Th1 cells, and regulatory T-cells were analyzed in these transgenic mice; and T-cell proliferation, adoptive transfer, and islet transplantation were performed to evaluate the PD-L1 transgene–mediated immune-protective mechanisms.RESULTS—The severity of insulitis in these transgenic mice is significantly decreased, disease onset is delayed, and the incidence of diabetes is markedly decreased compared with littermate controls. NOD/SCID mice that received lymphocytes from transgenic mice became diabetic at a slower rate than mice receiving control lymphocytes. Moreover, lymphocytes collected from recipients transferred by lymphocytes from transgenic mice revealed less proliferative potential than lymphocytes obtained from control recipients. Transgenic islets transplanted in diabetic recipients survived moderately longer than control islets.CONCLUSIONS—Our results demonstrate the protective potential of transgenic PD-L1 in autoimmune diabetes and illustrate its role in downregulating diabetogenic T-cells in NOD mice.Programmed death 1 (PD-1) is an immunoreceptor of the CD28/CTLA-4 family whose expression is induced in activated T- and B-cells and in macrophages (1,2). PD-1 has two cytoplasmic tyrosine motifs: one an immunoreceptor tyrosine-based inhibition motif and the other an immunoreceptor tyrosine-based switch motif (ITSM). On interaction of PD-1 with its ligands PD-L1 (B7-H1) or PD-L2 (B7-DC), the tyrosine-phosphorylated ITSM of PD-1 recruits a src homology 2 domain–containing tyrosine phosphatase 2, which mediates the dephosphorylation signaling and reduces lymphocyte activation (3). PD-1^−/− mice on different genetic backgrounds develop distinct autoimmune phenotypes, such as lupus-like glomerulonephritis/arthritis in C57Bl/6 (B6) mice or anticardiac troponin I–mediated dilated cardiomyopathy in Balb/c mice (4,5). These observations indicate that PD-1 is a critical negative regulator of lymphocyte activation and that the phenotype of PD-1 deficiency–induced autoimmunity is highly influenced by other genetic factors.Murine PD-L1 is expressed on many cell types, including stromal cells within many organs, but PD-L2 expression is much more restricted, occurring mainly in dendritic cells, activated monocytes, and macrophages (6,7). Although accumulating data indicate that both PD-L1/PD-1 and PD-L2/PD-1 signals can suppress T-cell proliferation and effector function by blocking cell cycle progression and cytokine production, signaling through PD-L1 interaction is more potent than that through PD-L2 (8). This is consistent with the observations that cytokine production, cytotoxic activity, and clonal expansion were significantly enhanced in T-cells and antigen-presenting cells from PD-L1^−/− mice, compared with cells from wild-type or PD-L2^−/− mice (9,10). Moreover, the PD-L1^−/− mice revealed an increased susceptibility to the induction of autoimmune diseases, such as experimental allergic encephalomyelitis (9), strongly suggesting a protective role of tissue PD-L1 in the maintenance of immune tolerance. Furthermore, treatment of nonobese diabetic (NOD) mice with a combination of agonistic PD-L1.Ig fusion protein and monoclonal antibodies (mAbs) to CD154 induced long-term islet allograft survival, whereas the inhibition of PD-L1–mediated signals by blocking antibody exacerbated autoimmune diabetes (11). Based on these findings, we hypothesize that transgenic expression of PD-L1 in an islet-specific manner may help in preventing T-cell–mediated islet destruction in NOD mice.To investigate the preventive and/or therapeutic potential of PD-L1 in autoimmune diabetes, we generated transgenic NOD mice overexpressing PD-L1 under control of an insulin promoter. Although a recent report demonstrated that local expression of transgenic PD-L1 on β-cells of B6 mice unexpectedly promotes organ-specific autoimmunity and transplant rejection (12), we hypothesized that overexpression of PD-L1 on islet cells in NOD mice would enhance inhibitory signaling through the PD-1–PD-L1 interaction and protect islet cells from lymphocyte attack. Our results demonstrate that transgenic PD-L1 on islet cells significantly ameliorates the severity of insulitis and incidence of diabetes in NOD mice. Interestingly, our results also indicate that local transgene expression not only protects islets in situ but also mediates a peripheral tolerance. Moreover, transgenic islets transplanted in diabetic recipients survived moderately longer than control islets. Overall, we demonstrate for the first time the preventive potential of transgenic PD-L1 in autoimmune diabetes and provide a theoretical basis for organ-specific genetic manipulation for disease prevention.     

Prognostic value of PD-1 and PD-L1 expression in patients with metastatic clear cell renal cell carcinoma

Objective

In renal cell carcinoma (RCC), several prognostic biomarkers have been identified and are under investigation. Several reports have shown that the expression of programmed death 1 (PD-1) and its ligand PD-L1 is associated with poor outcome for patients with RCC. The present study is aimed at evaluating the expression of PD-1 and PD-L1 and to investigate their clinical and prognostic significance in patients with clear cell RCC (CCRCC) having received molecular targeted therapies. In addition, we also evaluated the relationship between the expression of PD-1 and PD-L1 and intratumoral tumor infiltrating lymphocytes (TILs).

Role of tumor-associated macrophages in the progression of hepatocellular carcinoma

Recent studies have shown that the tumor microenvironment plays an important role in cancer progression. Tumor-associated macrophages (TAMs), in particular, have been found to be associated with tumor progression. Macrophages have multiple biological roles, including antigen presentation, target cell cytotoxicity, removal of foreign bodies, tissue remodeling, regulation of inflammation, induction of immunity, thrombosis, and endocytosis. Recent immunological studies have identified two distinct states of polarized macrophage activation: the classically activated (M1) and the alternatively activated (M2) macrophage phenotypes. Bacterial moieties such as lipopolysaccharides and the Th1 cytokine interferon-γ polarize macrophages toward the M1 phenotype. The M2 polarization was discovered as a response to the Th2 cytokine interleukin-4. In general, M2 macrophages exert immunoregulatory activity, participate in polarized Th2 responses, and aid tumor progression. TAMs have recently been found to play an important role in hepatocellular carcinoma (HCC) progression. Based on the properties of TAMs, obtained from pathological examination of resected specimens, we have identified new therapeutic approaches, involving the targeting of TAMs with adjuvant therapy after hepatic resection for HCC. This review discusses the roles of TAM in HCC progression and the possibility of new therapies targeting TAMs.     

循环肿瘤细胞PD-L1表达在非小细胞肺癌免疫治疗中的应用

肺癌是全世界发病率及病死率最高的恶性肿瘤。近年来,针对程序性死亡受体1(programmed cell death 1,PD-1)及其配体(programmed cell death-ligand 1,PD-L1)的免疫检查点抑制剂治疗显著改善了非小细胞肺癌(non-small cell lung cancer,NSCLC)患者的预后。然而在非选择人群中免疫治疗的客观应答率仅约20%,因此选择出免疫治疗潜在的获益人群非常重要。通过免疫组织化学检测肿瘤组织中PD-L1的表达可以在一定程度上预测免疫治疗的疗效,但是其仍有一定的局限性。最新临床研究表明循环肿瘤细胞(circulating tumor cell,CTC)上PD-L1的表达(PD-L1 expression in circulating tumor cells,CTC-PD-L1)是一种潜在的独立生物标志物,其可为NSCLC的免疫治疗提供重要信息。本文将对CTC-PD-L1检测技术及其在NSCLC患者免疫治疗效果中的预测价值及最新临床研究进展进行综述。