PD-1及其配体在原发性干燥综合征患者唇腺中的表达及临床意义

目的:观察干燥综合征(Sjogren's syndrome,SS)患者唇腺活检组织中程序性死亡分子-1(programmed death-1,PD-1)、程序性死亡配体-1(programmed death ligand-1,PD-L1)、程序性死亡配体-2(programmed death ligand-2,PD-L2)的表达,以及其与临床病理特征的相关性.方法:对所有患者和正常对照组的唇腺活检标本进行HE染色观察淋巴细胞浸润程度,免疫组织化学观察PD-1,PD-L1和PD-L2的表达.结果:SS患者唇腺活检组织中PD-1,PD-L1和PD-L2的表达较正常对照组明显增强.SS患者唇腺活检标本淋巴细胞的浸润程度与PD-1和PD-L2的表达强度无明显相关性,与PD-L1的表达强度呈正相关.SS患者疾病活动度评分与PD-1,PD-L1及PD-L2的表达强度均无明显相关性.SS患者疾病损害评分与PD-1的表达强度无明显相关性,与PD-L1和PD-L2的表达强度呈负相关.结论:PD-1,PD-L1及PD-L2在SS患者唇腺活检组织中的表达明显增强,PD-1/PD-L信号通路可能在SS的免疫病理损害中起重要作用.     

程序性死亡受体1在HIV感染和防治中的作用研究进展

程序性死亡受体1(programmed cell death-1,PD-1)是细胞表面的一种免疫抑制分子,与配体PD-L1或PD-L2相互作用,负向调控细胞和体液免疫应答。人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染后,PD-1在感染者外周血淋巴细胞表面表达上调,高水平表达的...     

趋化素样因子超家族成员6 的研究进展

含CKLF样MARVEL跨膜结构域基因6(CMTM6)是CMTMs家族的一员,可以介导程序性死亡受体1配体(PD-L1)的内含体再循环,维持PD-L1的稳定性。PD-L1作为肿瘤中重要的免疫抑制分子,与多种恶性肿瘤的发生密切相关。研究表明,CMTM6在多种肿瘤细胞和肿瘤基质中高表达,与PD-L1表达具有一致性。PD-L1除了参与PD-1/PD-L1轴的免疫抑制作用,还可以调节肿瘤细胞和抗原呈递细胞中的基因组稳定性,这提示CMTM6可能参与了PD-L1的调节过程而影响肿瘤的发生发展。本文就CMTM6的研究进展及其在肿瘤中的作用机制作一综述。     

PD-L1表达调控与肿瘤免疫治疗的研究进展

程序性细胞死亡蛋白1(programmed cell death protein 1,PD-1)/程序性死亡配体1(programmed death-ligand 1,PD-L1)是导致肿瘤免疫逃逸的重要免疫检查点分子,阻断PD-1/PD-L1可以重新激活细胞毒性T细胞对肿瘤的杀伤作用,是一种重要的肿瘤免疫治疗方式。肿...     

PD-1/PD-L在淋巴瘤中的研究进展

淋巴瘤是一组异质性的淋巴造血系统恶性肿瘤。程序性死亡受体1(programmed death-1,PD-1)及其配体(programmed death-ligand,PD-L)在T细胞介导的免疫应答过程中发挥重要作用。PD-1与PD-L1/PD-L2之间的相互作用可引起细胞凋亡以及T细胞耗竭,进而抑制抗肿瘤免疫应答。近年来研究发现以PD-1/PD-L1为靶点的免疫检查点抑制剂可有效地恢复T细胞功能,为肿瘤的治疗带来希望。该文就PD-1/PD-L在淋巴瘤中的免疫组化研究进展作一综述,以期为淋巴瘤的诊疗提供参考。     

膀胱尿路上皮癌中PD-L1和PD-L2的表达及临床意义

目的 探讨膀胱尿路上皮癌(urothelial bladder cancer,UBC)中程序性死亡配体-1(programmed death-ligand 1,PD-L1)以及程序性死亡配体-2(programmed death-ligand 2,PD-L2)的表达及临床意义.方法 采用免疫组化法检测58例UBC组织中...     

PD-1及PD-L1与肿瘤适应性免疫抵抗的研究进展

程序性死亡蛋白-1(programmed death protein 1,PD-1)与其配体程序性死亡配体1(programmed cell death-ligand 1,PD-L1)属于CD28/B7家族,是近年研究比较透彻的免疫检查点分子。PD-1/PD-L1通过调节外周组织中免疫反应的持续性和效价避免组织损伤并维持对于自身抗原的耐受。肿瘤细胞主动性抑制T细胞的机制称为适应性免疫抵抗(adaptive immune resistance),即肿瘤抗原特异性T细胞企图攻击肿瘤,但肿瘤细胞发生反应性改变(诱导表达PD-L1)从而避免免疫攻击。适应性免疫抵抗过程中的关键分子即为PD-1/PD-L1。PD-1/PD-L1抗体治疗已在临床试验中显示出良好的疗效,使阻断适应性免疫抵抗有望成为重要的肿瘤免疫治疗手段。分析肿瘤活检样本的基线免疫信息能指导制定个体化的免疫治疗方案。本文就PD-1/PD-L1的生物学结构、适应性免疫抵抗机制及相关临床决策等进行综述。     

舒尼替尼抑制小鼠骨髓来源树突状细胞表面PD-L1和PD-L2的表达

目的观察小鼠髓源性树突状细胞(DC)在舒尼替尼刺激下,其表面程序性死亡分子1配体1(PD-L1)和PD-L2的表达变化。方法取小鼠骨髓细胞,对照组加入二甲基亚砜,实验组分别加入(100、200、300)ng/m L舒尼替尼,刺激48 h,用流式细胞术检测DC表面PD-L1和PD-L2的表达水平。结果与对照组相比,实验组中成熟DC(m DC)和总DC(包括m DC和im DC)表面PD-L1的表达水平显著降低;表达PD-L1的未成熟DC(im DC)、m DC和DC百分比均显著降低,表达PD-L2的m DC百分比显著降低;表达PD-L2的DC百分比在100 ng/m L、300 ng/m L舒尼替尼组中显著降低。结论舒尼替尼可显著降低小鼠DC表面PD-L1、PD-L2的表达。     

PD-1/PD-L1检测点抑制剂抵抗机制的研究进展北大核心CSCD

机体的免疫系统可以识别并摧毁肿瘤,但肿瘤为了逃避免疫攻击可以进化。当前以细胞毒性T淋巴细胞相关蛋白4(cytotoxic T-lymphocyte-associated protein 4,CTLA4)或程序性死亡分子受体1(programmed death 1,PD-1)及程序性死亡分子配体1(programmed death 1 ligand,PD-L1)为靶点的免疫治疗成为了强有力的新治疗方案[1]。     

PD-1及其配体在实体肿瘤中的应用

程序性死亡生长因子-1( PD-1/CD279)是新近研究的热门分子,PD-1与其配体PD-L1/2(B7-H1/CD274)最终导致淋巴细胞“耗尽”以及诱导免疫耐受。 PD-L1在肿瘤细胞中可呈高表达,其异常表达与患者预后密切相关。最近越来越多的研究关注于PD-1、PD-L1/2在各类实体肿瘤中的表达,日前美国食品及药物管理局 FDA 批准 Keytruda ( pembroli-zumab)用于治疗对其它药物治疗无效的晚期或无法切除的黑色素瘤患者,其机制是Keytruda能阻断PD-1细胞通路,这些均提示针对PD-1、PD-L1/2分子治疗可能成为肿瘤治疗的突破点,且PD-1、PD-L1/2在实体肿瘤的表达可能成为预后评估新生物学的标志物。该文现就PD-1、PD-L1/2在肿瘤中的研究新进展作一综述。     

B7家族新成员HHLA2在人类恶性肿瘤中的研究现状

HHLA2(human endogenous retrovirus-H long terminal repeat-associating 2)是第二信号分子B7家族的一个新成员,与不同的受体结合提供T细胞活化的共抑制或共刺激信号.研究表明,HHLA2很少表达于人类正常组织,却高表达于多种人类恶性肿瘤组织,提示HHLA2可能参与免疫逃逸,对恶性肿瘤的发生、发展、转移及预后有一定影响,可能是恶性肿瘤免疫治疗的一个新靶点.因而,深入研究H H L A 2在多种恶性肿瘤中的表达情况有重要意义.     

B7-H4 and HHLA2, members of B7 family,are aberrantly expressed in EGFR mutated lung adenocarcinoma

BackgroundIn order to find new immune targets for lung cancer with different EGFR mutant status, we describe differential expression profiles of checkpoint molecules of the new discovery B7 family member to find new immune targets for lung cancer with different EGFR statuses.MethodsWe performed immunohistochemistry with antibodies of B7-H3, B7-H4, VISTA, B7-H6, HHLA2, IDO-1, PD-L1 and CD8 in lung adenocarcinoma tissues constructed from 372 cases in the discovery cohort and 231 cases in the validation set. The differential expression profiles of these indices in EGFR mutant and wild-type lung adenocarcinoma was described and compared.ResultsIn the discovery cohort, the median IHC scores of B7-H4 and HHLA2 for the EGFR mutant group were significantly higher than those in the wild-type group (median score [interquartile range], mutant vs. wild type: 3.250 [0−7.000] vs. 5.000 [1.000−7.000], P = 0.045 for B7-H4; 8.000 [6.000−10.500] vs. 7.000 [5.000−8.630] P = 0.003 for HHLA2). Meanwhile, the median IHC scores of IDO-1 and PD-L1 in the wild-type group were significantly higher than those in the mutant group (median score [interquartile range], mutant vs. wild type: 1.000 [0−5.000] vs. 3.000 [0−8.500], P = 0.000 for IDO-1; 0 [0−3.500] vs. 3.000 [0−6.000], P = 0.000 for PD-L1). Results above was confirmed in the discovery cohort. The increased CD8 and decreased HHLA2 expression levels were associated with long disease-free survival in lung adenocarcinoma (P = 0.000 for CD8 expression and P = 0.004 for HHLA2 expression).ConclusionsB7-H4 and HHLA2 are promising immune targets for lung adenocarcinoma, especially for patients with EGFR mutation.     

The expression of programmed death-ligand 1 and programmed death-ligand 2 in endometrial carcinosarcoma: Correlation with mismatch repair protein expression status,tumor-infiltrating lymphocyte infiltration,and clinical outcomes

BackgroundEndometrial carcinosarcomas have high malignant potential with a high recurrence rate and poor prognosis. Immunotherapy may be a promising treatment option. The aim of this study is to evaluate the expression of PD-L1/PD-L2 and its relationship to mismatch repair (MMR) protein status and tumor-infiltrating lymphocyte (TIL) density.MethodsWe performed immunohistochemical analyses of PD-L1 (clone 22C3), PD-L2 (clone TY25), MSH-2, MSH-6, PMS-2, and MLH-1 in 77 tumors. We count TILs using CD8 antibody. Clinicopathologic features were recorded and statistically correlated with immunohistochemical results. Kaplan-Meier analyses were used to analyze the prognosis.ResultsWhile PD-L1 positivity was seen more commonly in MMR protein deficient tumors (p = 0.010), PD-L2 positivity was seen more commonly in MMR protein proficient tumors (p = 0.003). PD-L1 positivity was also found to be more common in carcinosarcoma with high TIL infiltration. PD-L2 positivity was associated with decreased overall survival (OS) rates (p = 0.043, p = 0.043, respectively), whereas the PD-L1 positivity and TIL density were not significantly associated with OS rate. The OS rate of patients with MMR protein proficient tumors was significantly lower compared with those with MMR protein deficient tumors (p = 0.042). The lower TILs infiltration was associated with a shorter disease-free survival (DFS) rate. PD-L1 and PD-L2 positivity did not affect the DFS rate.ConclusionsPD-L1/PD-L2 might be a better target for immunotherapy in endometrial carcinosarcoma. PD-L2 positivity was also associated with a worse clinical outcome in patients with endometrial carcinosarcoma, suggesting that PD-L2 status can be used to predict clinical behavior. Further studies are needed to elucidate the relationship between PD-L1/PD-L2 expression and therapeutic response.     

Expression and function of PD-1 in human γδ T cells that recognize phosphoantigens

Programmed cell death-1 (PD-1) is an inhibitory receptor and plays an important role in the regulation of αβ T cells. Little is known, however, about the role of PD-1 in γδ T cells. In this study, we investigated the expression and function of PD-1 in human γδ T cells. Expression of PD-1 was rapidly induced in primary γδ T cells following antigenic stimulation, and the PD-1(+) γδ T cells produced IL-2. When PD-1(+) γδ T cells were stimulated with Daudi cells with and without programmed cell death ligand-1 (PD-L1) expression, the levels of IFN-γ production and cytotoxicity in response to PD-L1(+) Daudi cells were diminished compared to the levels seen in response to PD-L1(-) Daudi cells. The attenuated effector functions were reversed by anti-PD-L1 mAb. When PD-1(+) γδ T cells were challenged by PD-L1(+) tumors pretreated with zoledronate (Zol), which induced γδ TCR-mediated signaling, the resulting reduction in cytokine production was only slight to moderate compared to the reduction seen when PD-1(+) γδ T cells were challenged by PD-L1(-) tumors. In addition, cytotoxic activity of PD-1(+) γδ T cells against Zol-treated PD-L1(+) tumors was comparable to that against Zol-treated PD-L1(-) tumors. These results suggest that TCR triggering may partially overcome the inhibitory effect of PD-1 in γδ T cells.     

Tumor PD-L1 co-stimulates primary human CD8(+) cytotoxic T cells modified to express a PD1:CD28 chimeric receptor

Tumors exploit immunoregulatory checkpoints that serve to attenuate T cell responses as a means of circumventing immunologic rejection. Programmed death ligand 1 (PD-L1) is a negative regulator of T cell function and is frequently expressed by solid tumors. By engaging programmed death 1 (PD-1) on activated T cells, PD-L1(+) tumors directly render tumor-specific T cells, including adoptively transferred T cells, functionally exhausted. As a strategy to overcome tumor PD-L1 effects on adoptively transferred T cells, we sought to convert PD-1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with that of CD28. Rather than becoming exhausted upon engagement of PD-L1(+) tumors, we hypothesized that CD8(+) cytotoxic T lymphocytes (CTL) genetically modified to express this PD1:CD28 chimera would exhibit enhanced functional attributes. Here we show that cell surface expressed PD1:CD28 retains the capacity to bind PD-L1 resulting in T cell costimulation as evidenced by increased levels of ERK phosphorylation, augmentation of cytokine secretion, increased proliferative capacity, and enhanced expression of effector molecule Granzyme B. We provide evidence that this chimera could serve as a novel engineering strategy to overcome PD-L1 mediated immunosuppression.     

Expression of programmed cell death 1/programmed cell death ligand 1 in the tumor microenvironments of primary gastrointestinal diffuse large B cell lymphomas

Background

Gastrointestinal diffuse large B cell lymphoma (GI DLBCL) is the most common gastrointestinal lymphoma. However, there has not been a comprehensive investigation into the expression patterns of programmed cell death 1 (PD-1) and programmed cell death ligand 1(PD-L1) in GI DLBCL tissues.

MMR deficient undifferentiated/dedifferentiated endometrial carcinomas showing significant programmed death ligand-1 expression (sp 142) with potential therapeutic implications

BackgroundUterine undifferentiated (UEAC)/dedifferentiated (DEAC) carcinomas are rare malignant neoplasms. They appear to pursue an aggressive clinical course with an advanced stage at presentation. Recently, it was discovered that the use of immunotherapeutic drugs targeting programmed cell death protein 1 (PD1)/programmed death ligand-1 (PD-L1) was associated with improved survival in several types of cancer (especially in patients with mismatch-repair (MMR) deficient patients). Whether these findings can be applied to UEAC/DEAC remains a question. Herein, the aim of this study is to evaluate the expression of PD-L1/PD-1 in UEAC/DEAC and its relationship to MMR status. This could offer useful therapeutic information.DesignReview of endometrial carcinoma (EC) diagnosed over the period of 2011 to 2017 in our institution identified 14 UEAC/DEAC cases (n=14). All cases had immunohistochemistry performed for MMR (MLH1, PMS2, MSH2 and MSH6), PD-L1 and PD-1. The protein expression was examined and in DEAC cases both the undifferentiated component and the low grade component were recorded separately. The expression of PD-L1 and PD-1 was scored in both the tumor and the peritumoral lymphocyte infiltration.ResultsOverall variable degrees of tumoral or immune stromal PD-L1 staining (from 1% to 5%), was present in 50.0% (7/14) of UC/DEACs. Seven cases (50%) were PD-1 positive (immune stromal). Five cases (35.7%) showed co-expression of PD-1 and PD-L1 (Figure 1). Worth noting is that PD-1 staining was exclusively present in peritumoral immune cells. Following this the 14 cases were further divided into MMR deficient and MMR proficient groups (Table 1). A total of 8 cases had MMR deficiency (57.1%). There was a statistically significant association for PD-L1 positivity in the MMR deficiency group (p=0.05). However there was no statistically significant differences regarding PD-1 positivity between MMR groups.ConclusionsPD-L1 and PD-1 were expressed in majority of MMR-deficient UEAC /DEAC cases. PD-L1 was not expressed in MMR-proficient carcinomas. These findings might help support potential immunotherapy trials in MMR-deficient UEAC /DEAC.     

The role of immune checkpoint receptors in the malignant phenotype of cutaneous T cell lymphoma

Immune checkpoint receptors (ICR) modulate the immune response and are critical hubs for immunotherapy. However, data on their role in T lymphoid malignancies, such as cutaneous T cell lymphoma (CTCL), is sparse. We aimed to explore the role of ICR in the malignant features of transformed T lymphocytes and evaluate the effect of ICR-targeting monoclonal antibodies, often used as immunotherapy for solid tumors. We used the CTCL cell line HH and the Sézary cell line Hut78 to examine ICR expression and the effects of ICR inhibition on cell viability and proliferation. Despite their shared T cell progeny, the different CTCL cell lines exhibit markedly different ICR expression profiles. Programmed cell death-ligand 1 (PD-L1) was expressed by both cell lines, while programmed death-1 (PD-1) was expressed only by the HH cell line. Common to all malignant T cells was an autonomous hyper-proliferative state that did not require T cell receptor stimulation. A monoclonal antibody blocking PD-1 had a small but statistically significant augmenting effect on T cell proliferation. Of note, when the cells were exposed to ionizing radiation, healthy lymphocytes and those derived from the HH cell line were salvaged by anti-PD-L1. We show a regulatory role of ICR, mainly PD-1 and its ligand PD-L1, on cutaneous T cell malignancy.

     

High PD-L1 expression in gastric cancer (GC) patients and correlation with molecular features

BackgroundThe programmed death receptor ligand 1 (PD-L1) immunohistochemistry (IHC) 22C3 pharmDx assay is a widely used selection method for pembrolizumab treatment in gastric cancer (GC) patients, especially in the U.S. The present study investigated the relationship between PD-L1 expression and the clinical features, molecular markers, and molecular subtypes of GC.MethodsPD-L1 expression was assessed based on combined positive score (CPS) using PD-L1 IHC 22C3 pharmDx in the Asian Cancer Research Group (ACRG) GC cohort (N = 300), which has been previously genomically profiled. PD-L1 positivity was defined as PD-L1 CPS ≥ 1. The association between PD-L1 expression and clinical features, tumor burden, and molecular subtypes (ACRG and The Cancer Genome Atlas [TCGA]) was analyzed.ResultsOf the 300 tumors, 178 (59.3 %) had PD-L1 CPS ≥ 1 and 122 (40.7 %) had PD-L1 CPS < 1. PD-L1 CPS ≥ 1 was significantly associated with stage I tumor (P = 0.022), high microsatellite instability (MSI-H) (P < 0.001), Epstein-Barr virus (EBV) positivity (P = 0.008), and positive Helicobacter pylori status (P = 0.001). PD-L1 CPS ≥ 1 was observed in 96/193 (49.7 %) EBV-negative/microsatellite stable (MSS) tumors. In gene expression profiling, PD-L1 CPS was highly correlated with mutational load (P < 0.001) as well as EBV (P < 0.001) and MSI subtypes (P < 0.001); 27/300 (9%) GC patients had a very high PD-L1 (≥ 20) score (MSI-H, n = 10; EBV, n = 6; and non-EBV/MSS, n = 11). OS was longer in patients with PD-L1 CPS ≥ 1 tumors than in those with PD-L1 CPS < 1 tumors (median OS not reached vs. 40 months; P = 0.008; log-rank test).ConclusionsPD-L1 is expressed in 59.3 % of GC patients and is associated with MSI and EBV positivity. These results provide a basis for identifying GC patients who may benefit from anti-PD-1/PD-L1 therapy.