Regulatory T cells and the PD-L1/PD-1 pathway mediate immune suppression in malignant human brain tumors

The brain is a specialized immune site representing a unique tumor microenvironment. The availability of fresh brain tumor material for ex vivo analysis is often limited because large parts of many brain tumors are resected using ultrasonic aspiration. We analyzed ultrasonic tumor aspirates as a biosource to study immune suppressive mechanisms in 83 human brain tumors. Lymphocyte infiltrates in brain tumor tissues and ultrasonic aspirates were comparable with respect to lymphocyte content and viability. Applying ultrasonic aspirates, we detected massive infiltration of CD4⁺FoxP3⁺CD25^high CD127^low regulatory T cells (Tregs) in glioblastomas (n = 29) and metastatic brain tumors (n = 20). No Treg accumulation was observed in benign tumors such as meningiomas (n = 10) and pituitary adenomas (n = 5). A significant Treg increase in blood was seen only in patients with metastatic brain tumors. Tregs in high-grade tumors exhibited an activated phenotype as indicated by decreased proliferation and elevated CTLA-4 and FoxP3 expression relative to blood Tregs. Functional analysis showed that the tumor-derived Tregs efficiently suppressed cytokine secretion and proliferation of autologous intratumoral lymphocytes. Most tumor-infiltrating Tregs were localized in close proximity to effector T cells, as visualized by immunohistochemistry. Furthermore, 61% of the malignant brain tumors expressed programmed death ligand-1 (PD-L1), while the inhibitory PD-1 receptor was expressed on CD4⁺ effector cells present in 26% of tumors. In conclusion, using ultrasonic tumor aspirates as a biosource we identified Tregs and the PD-L1/PD-1 pathway as immune suppressive mechanisms in malignant but not benign human brain tumors.     

基于PD-1/PD-L1靶点的肿瘤免疫治疗研究进展

近年来的研究显示,肿瘤免疫治疗在恶性肿瘤的治疗上成效显著,疗效优于传统的化疗和放疗.程序性死亡受体-1(programmed death 1,PD-1)和程序性死亡受体配体-1(programmed death-ligand 1,PD-L1)这对免疫共抑制分子作为肿瘤免疫治疗的靶点备受关注,PD-L1在一些肿瘤细胞中的...     

Expression of programmed cell death ligand 1 (PD-L1) and prevalence of tumor-infiltrating lymphocytes (TILs) in chordoma

Chordomas are primary malignant tumors of the notochord that are resistant to conventional chemotherapy. Expression of programmed cell death ligand 1 (PD-L1), prevalence of tumor-infiltrating lymphocytes (TILs), and their clinical relevance in chordoma remain unknown. We evaluated PD-L1 expression in three chordoma cell lines and nine chordoma tissue samples by western blot. Immunohistochemical staining was performed on a chordoma tissue microarray (TMA) that contained 78 tissue specimens. We also correlated the expression of PD-L1 and TILs with clinical outcomes. PD-L1 protein expression was demonstrated to be induced by IFN-γ in both UCH1 and UCH2 cell lines. Across nine human chordoma tissue samples, PD-L1 protein was differentially expressed. 94.9% of chordoma samples showed positive PD-L1 expression in the TMA. The expression score of PD-L1 for metastatic chordoma tumors was significant higher as compared with non-metastatic chordoma tumors. Expression of PD-L1 protein significantly correlates with the presence of elevated TILs, which correlates with metastasis. In summary, our study showed high levels of PD-L1 are expressed in chordoma, which is correlated with the prevalence of TILs. The current study suggests targeting PD-L1 may be a novel immunotherapeutic strategy for chordoma clinical trials.     

PD-1/PD-L1抑制剂在恶性黑色素瘤（新）辅助治疗中的研究进展

恶性黑色素瘤是一种具有较高复发率及死亡率的实体肿瘤。目前针对Ⅱ～Ⅲ期黑色素瘤的治疗仍是以外科手术为主,由于缺乏有效的(新)辅助治疗手段,高危黑色素瘤患者的5年生存率仅有30%～70%。程序性死亡因子1(PD-1)和程序性死亡因子配体1(PD-L1)是重要的免疫检验点共抑制分子,通过抑制T细胞的激活和增殖通路参与了肿瘤的免疫逃逸。近些年来包括Nivolumab和Pembrolizumab在内的多种PD-1/PD-L1抑制剂研发获批上市,并在晚期黑色素瘤的治疗中表现出显著的疗效。因此多项针对PD-1/PD-L1抑制剂在高危黑色素瘤患者(新)辅助治疗的临床试验正积极开展。本文主要对近年来相关研究进行了回顾与总结,探讨PD-1/PD-L1抑制剂在黑色素瘤(新)辅助治疗应用的前景和可能发展的方向。     

程序性死亡受体-1及其配体在血液肿瘤中的研究进展

程序性死亡受体-1(programmed death-1,PD-1)及配体PD-L1为CD28/B7免疫球蛋白超家族负性协同刺激分子成员,在许多肿瘤细胞及其相关细胞表面高表达.近年来免疫治疗成为肿瘤治疗的新热点,其中PD-l及配体PD-L1为靶点的免疫抑制药物在各类肿瘤临床试验中显示出了良好的疗效和安全性.本文将对近年来其在白血病、淋巴瘤等血液系统疾病治疗中的研究现状作一综述,以期为血液系统疾病的治疗提供新的方法.     

PD-1/PD-L1在食管鳞癌中的研究进展

食管癌的发病率和死亡率均较高,也是最难治疗和治愈的恶性肿瘤之一。当前,免疫检查点抑制剂在肿瘤治疗中取得了突破进展,相关研究已成为热点,针对免疫检查点“程序性死亡分子1”(PD-1)及其配体PD-L1抗体的临床研究也正在广泛开展,本文就PD-1/PD-L1在食管鳞癌中的研究进展做一综述。     

PD-1/PD-L1介导的肿瘤免疫逃逸在肿瘤微环境中的研究进展

肿瘤免疫逃逸在肿瘤的发生发展中起重要作用.近年来,作为肿瘤免疫逃逸的众多机制之一的免疫抑制,也成为了研究的热点.PD-1/PD-L1信号传导途径是肿瘤免疫抑制的重要组成部分,具有抑制T淋巴细胞的活化和增强肿瘤细胞免疫耐受的作用,从而达到肿瘤免疫逃逸.因此,靶向PD-1/PD-L1途径是癌症治疗的重要策略,本文总结了PD...     

Expression of PD-1/PD-L1 in lung adenocarcinoma and its clinical significance

Objective This study aimed to investigate PD-1/PD-L1 expression in lung adenocarcinoma and its relationship with EGFR/KRAS mutation.Methods The expression levels of PD-1 and PD-L1 in lung adenocarcinoma were detected.Clinicopathological parameters were collected and followed up.The effects of PD-1 and PD-L1 expression on clinicopathological parameters and prognosis of patients with lung adenocarcinoma were statistically analyzed.Results PD-L1 and PD-1 were mainly located in the membrane and cytoplasm of tumor cells.The positive expression rates of PD-1 and PD-L1 were 53%and 40%,respectively.Positive PD-1 expression had a significant effect on the incidence of KRAS mutation(P<0.05),while PD-L1 expression significantly affected the incidence of EGFR mutation(P<0.05).Overexpression of PD-1 and PD-L1 had a significant negative effect on disease-free survival(DFS)in patients with lung adenocarcinoma(P<0.05)but had no significant effect on overall survival(P>0.05).EGFR gene mutation,high PD-1 expression,high PD-L1 expression,N stage,and AJCC stage were independent risk factors of DFS(P<0.05).Conclusion High PD-1/PD-L1 expression is closely related to the occurrence of lung adenocarcinoma and can be used as an independent factor to assess the prognosis of patients with lung adenocarcinoma.There were negative correlations between PD-L1 expression and EGFR mutation and between PD-1 expression and KRAS mutation.     

Review and prospect of immune checkpoint blockade therapy represented by PD-1/PD-L1 in the treatment of clear cell renal cell carcinoma

As a common tumor of the urinary system, the morbidity and mortality related to renal carcinoma, are increasing annually. Clear cell renal cell carcinoma (CCRCC) is the most common subtype of renal cell carcinoma, accounting for approximately 75% of the total number of patients with renal cell carcinoma. Currently, the clinical treatment of ccRCC involves targeted therapy, immunotherapy, and a combination of the two. In immunotherapy, PD-1/PD-L1 blocking of activated T cells to kill cancer cells is the most common treatment. However, as treatment progresses, some patients gradually develop resistance to immunotherapy. Meanwhile, other patients experience great side effects after immunotherapy, resulting in a survival status far lower than the expected survival rate. Based on these clinical problems, many researchers have been working on the improvement of tumor immunotherapy in recent years and have accumulated numerous research results. We hope to find a more suitable direction for future immunotherapy for ccRCC by combining these results and the latest research progress.     

免疫检查点PD-1／PD-L1通路在小细胞肺癌中的作用

小细胞肺癌（SCLC）主要的特点为生长迅速且早期易发生广泛转移。尽管SCLC对于化疗和放疗敏感,但几乎所有的患者均在治疗后发生复发转移,预后差。免疫检测点抑制剂,尤其程序化细胞死亡受体-1（PD-1）／程序化细胞死亡配体-1（PD-L1）拮抗剂在SCLC的临床前和临床研究中均获得了良好效果,并且能够延长患者生存。免疫检测点疗法作为一种新兴的方法在未来可能会改变SCLC治疗模式。此外,有限的数据显示出PD-L1表达可能成为筛选获益人群一个有效的生物标记物。本文总结PD-L1作为标记物的发展历程,并同时阐述PD-1／PD-L1抑制剂在SCLC治疗中的进展。     

PD-1/PD-L1在三阴乳腺癌中的研究进展

三阴乳腺癌特指雌激素受体、孕激素受体及人表皮生长因子受体2均阴性的乳腺癌患者,由于其对内分泌治疗无效,使其临床预后极差,因此,探索新的治疗方法尤为重要.近年来,肿瘤的免疫治疗已成为继放疗、化疗和手术治疗之后的第4种有效的治疗方法.研究表明,大约20%的三阴乳腺癌表达PD-L1,在介导肿瘤细胞免疫逃逸中起重要作用.本文就PD-1及其配体PD-L1在三阴乳腺癌中的表达、表达机制及其运用作一综述.     

生物标志物在阻断PD-1/PD-L1通路治疗肿瘤中的预测性作用

确定预测PD-1/PD-L1通路阻断治疗临床反应的生物标志物有助于患者筛查和个体化治疗.研究证明治疗前肿瘤组织中肿瘤细胞和肿瘤浸润淋巴细胞PD-L1的高表达,肿瘤间CD8+T细胞的大量浸润以及肿瘤细胞基因高突变负荷的患者阻断PD-1/PD-L1通路治疗的临床疗效更明显,这些生物标志物有望成为筛查肿瘤患者的指标.     

免疫治疗相关蛋白PD-1/PD-L1在三阴性乳腺癌中的表达及临床意义

目的探讨程序性死亡受体1(PDCD1,也称PD-1)及程序性死亡受体配体1(PDCD1LG1,也称PD-L1)在三阴性乳腺癌中的表达情况及其临床意义。方法收集39例三阴性乳腺癌患者和39例非三阴性乳腺癌患者的乳腺癌组织,采用免疫组织化学法检测不同乳腺癌组织中PD-1、PD-L1的表达情况,并对PD-1、PD-L1表达情况与三阴性乳腺癌患者临床特征的关系进行分析。结果三阴性乳腺癌组织中PD-1和PD-L1的阳性表达率均高于非三阴性乳腺癌组织(P﹤0.05)。不同年龄、绝经情况、组织学分级、肿瘤直径、淋巴结转移情况、肿瘤侵犯神经情况及脉管内癌栓情况三阴性乳腺癌患者的PD-1和PD-L1阳性表达率比较,差异均无统计学意义(P﹥0.05)。结论在三阴性乳腺癌中,PD-1、PD-L1具有较高的阳性表达率,检测PD-1和PD-L1的表达对早期诊断三阴性乳腺癌可能具有积极意义,同时,阻断PD-1和PD-L1信号通路可能成为三阴性乳腺癌潜在的治疗靶点。     

PD-1/PD-L1抑制剂在前列腺癌免疫治疗中的研究进展

前列腺癌（prostate cancer,PCa）发病率呈逐年上升趋势,前列腺癌免疫治疗已成为继外科、放疗、化疗之后的第四种治疗方法。作为当今肿瘤免疫治疗领域最具有研究前景的免疫检查点抑制剂中的程序性死亡受体-1（programmed cell death-1,PD-1）/程序性死亡配体-1（programmed cell death-ligand1,PD-L1）抑制剂,通过阻断PD-1与其配体PD-L1结合,从而终止T细胞的负性调控信号,使T细胞的活性恢复,进而逆转肿瘤免疫逃逸机制,恢复自身免疫应答,最后起到抑制和杀伤肿瘤的作用。本文就目前应用于前列腺癌临床试验的PD-1/PD-L1抑制剂的现况和临床疗效研究进展进行综述。      

PD-1/PD-L1在肝细胞癌治疗中的研究进展

肝细胞癌（简称肝癌）起病隐匿,进展迅速,容易复发和转移。较长一段时间以来,传统的治疗手段难以进一步提高肝癌病人的预后,而免疫治疗被认为是最有希望解决这一难题的新型疗法。免疫检查点是肿瘤免疫逃逸的主要机制之一。其中,PD-1/PD-L1是抗肿瘤免疫治疗的重要靶点。近年来,基于PD-1/PD-L1信号通路的免疫疗法在实体肿瘤或血液系统恶性肿瘤中显示出令人振奋的抗癌作用。本文对PD-1/PD-L1在肝癌治疗中的相关研究进行综述,探讨PD-1/PD-L1阻断在肝癌治疗中的应用前景。     

PD-L1和PD-1作为治疗结直肠癌的免疫检查新靶点的研究进展

免疫抗癌疗法是一种新的治疗实体肿瘤的方法。在这个新的领域,免疫系统里作为负向调节因子的免疫检查位点,在抗肿瘤免疫反应领域中起着重要的作用。因此,诸如抗细胞毒性T淋巴细胞相关抗原4(CTLA-4)、程序性细胞死亡蛋白（PD-1）、程序性细胞死亡蛋白配体1（PD-L1）,现在已经研发出了针对前述这三者免疫检查位点的阻断因子,用于抗肿瘤的药物,在临床前期研究和临床研究中有着可喜的成果。本文综述关于在结直肠癌中免疫检查位点阻断剂的生物背景和临床研发最新进展。关于阻断PD-1和PD-L1的临床前期试验结果的前景令人充满希望,尤其是在带有微卫星不稳定性（MSI）的结直肠癌患者中更加明显。接下来进一步深入开展的临床试验将证实这些初步结果,并且评估这二者联合治疗方法的可行性和确认这两个生物标记物作为免疫检查位点阻断剂的效应在哪些人群中更有可能受益或更加抵抗。     

PD-L1在结直肠癌肿瘤细胞、肿瘤浸润免疫细胞中的表达与临床病理特征及预后的相关性

目的:探讨结直肠癌（colorectal cancer,CRC）原发灶肿瘤细胞（tumor cells,TC）、肿瘤浸润免疫细胞（tumor-infiltrating immune cells,TIIC）中程序性死亡-配体1（programmed death-ligand 1,PD-L1）的表达与临床病理特征及预后的相关性。方法:采用免疫组化法检测 2018-2021年我院72例行结直肠癌根治性切除术且病理证实的癌组织TC、TIIC中PD-L1的表达,分析其与临床病理特征及总生存期（overall survival,OS）的关系。结果:72例结直肠癌TC PD-L1阳性率为6.9%,与肿瘤分化程度相关。TIIC PD-L1阳性率为48.6%,与术前血CEA、CA199水平有关。Kaplan-Meier 及 Log-rank 结果显示,患者OS与分化程度、淋巴结转移、肝转移、TIIC PD-L1表达有关（P＜0.05）,TIIC PD-L1阳性患者比阴性患者OS长。Cox单因素和多因素回归分析显示:分化程度、淋巴结转移、肝转移、TIIC PD-L1 表达是影响CRC患者 OS 的独立预后因素。结论:PD-L1 在CRC TC及TIIC中均表达,TIIC PD-L1阳性患者比阴性患者OS长。TIIC PD-L1的表达更能反应肿瘤免疫微环境,为免疫治疗疗效预测、CRC预后预测提供参考。     

PD-1/PD-L1抑制剂在晚期肝细胞肝癌治疗中的研究进展

晚期原发性肝细胞肝癌(hepatocellular carcinoma,HCC)的系统治疗主要包括靶向治疗、化疗以及免疫治疗。近3年,程序性死亡受体-1(programmed death receptor-1,PD-1)/程序性死亡受体-1配体(programmed death receptor-1 ligand,PD-L1)抑制剂在晚期HCC治疗中取得突破性进展。纳武单抗(nivolumab)和帕博利珠单抗(pembrolizumab)先后被美国食品药品管理局(FDA)批准用于HCC二线治疗。多个PD-1/PD-L1抑制剂联合系统治疗的Ⅰ、Ⅱ期临床研究初步显示出较好的疗效和安全性。阿特珠单抗(atezolizumab)联合贝伐单抗一线治疗成为首个在Ⅲ期临床研究中证实优于现有标准治疗索拉非尼的全新疗法。本文就近年PD-1/PD-L1抑制剂在晚期HCC治疗中的研究进展进行概述。     

PD-1/PD-L1在肿瘤中的机制研究及其在甲状腺癌中的诊治价值

程序性死亡受体1(PD-1)和程序性死亡受体配体1(PD-L1)参与免疫检查点调节,与肿瘤的发生和发展密切相关。在甲状腺癌中,PD-L1的表达及PD-1阳性T细胞的增多可能预示着更高的侵袭性与更大的复发风险。抗PD-1/PD-L1治疗在许多肿瘤中已有显著疗效,但在甲状腺癌方面的疗效还比较局限,需要寻找能够更好预测疗效的生物标志物。进一步了解PD-1/PD-L1的作用机制及其在甲状腺癌中的诊治价值以及与其疗效相关的生物标志物,可为甲状腺癌患者提供新的治疗方法与思路。     

雷帕霉素对人红白血病HEL细胞外泌体及PD-1/PD-L1的影响

目的 探讨雷帕霉素（Rapa）对JAK2 V617F阳性HEL细胞外泌体中JAK2、ABCA3及免疫检查点PD-1/PD-L1的影响。方法 体外培养人红白血病HEL细胞（JAK2 V617F阳性）,分别加入浓度为10、50和100 nmol/L的Rapa,设立对照组。CCK-8检测细胞增殖抑制率,最终确定细胞增殖抑制率选用浓度为10及50 nmol/L的Rapa干预细胞。外泌体试剂盒提取外泌体,Western blot及流式细胞术鉴定外泌体,荧光定量PCR检测外泌体中JAK2、ABCA3和PD-1、PD-L1 mRNA变化,流式细胞术检测外泌体PD-1/PD-L1蛋白表达。结果 外泌体试剂盒提取的外泌体均表达特征性的CD9、CD63、CD81蛋白,符合外泌体一般特征。HEL细胞外泌体中能够检测到JAK2 mRNA;Rapa能够减少HEL细胞外泌体产生,剂量依赖性降低外泌体中JAK2、ABCA3及PD-L1 的相对表达量,抑制外泌体PD-L1蛋白表达,对PD-1蛋白表达无明显影响。结论 HEL细胞可能通过外泌体传递JAK2突变基因信号,Rapa能够减少外泌体产生,进而抑制外泌体传递JAK2突变信号,抑制PD-L1蛋白表达。