PD-1/PD-L1在实体肿瘤组织中表达的研究进展

程序性死亡受体配体1（programmed death ligand 1,PD-L1）是一种参与免疫抑制通路的分子,在较多实体肿瘤细胞及其周围T淋巴细胞表面显著表达,能够与其受体程序性死亡受体1（programmed death-1,PD-1）结合,抑制肿瘤组织周围的免疫微环境,促使肿瘤细胞逃避免疫监视作用。本文就PD-1/PD-L1在不同实体肿瘤组织中表达的研究进展作一综述。     

PD-1/PD-L1治疗非小细胞肺癌的研究进展

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-ligand 1,PD-L1）信号通路与肿瘤免疫逃逸密切相关,针对PD-1/PD-L1通路的免疫检查点抑制剂为非小细胞肺癌（non-small cell lung cancer,NSCLC）患者提供了一种新的治疗选择,并且显示出良好的疗效和安全性。本文对PD-1/PD-L1抑制剂治疗NSCLC的临床研究进展进行综述。      

PD-1/PD-L1免疫检查点抑制剂致心脏毒性的研究进展

心脏毒性是抗肿瘤药物的严重不良反应,随着抗肿瘤药物的不断发展,免疫检查点抑制剂已被应用于多种癌症的治疗,特别是程序性死亡受体1（PD-1）或程序性死亡配体1（PD-L1）免疫检查点抑制剂近年来受到广泛关注,本文将从PD-1及PD-1/PD-L1免疫检查点抑制剂概述、PD-1/PD-L1免疫检查点抑制剂致心脏毒性的表现及可能机制的探索、心脏毒性的检测方法和PD-1/PD-L1所致心脏毒性的治疗等方面进行综述。     

PD-1/PD-L1通路抑制剂治疗进展期胃癌的研究进展

胃癌是危害人类健康的恶性肿瘤之一,对于早期胃癌而言,手术联合化疗效果显著,而对于进展期胃癌,其效果并不理想。程序性死亡受体-1（programmed cell death-1,PD-1）/程序性死亡受体配体-1（prorammed cell death ligand 1,PD-L1）通路的发现为进展期胃癌患者的治疗提供了希望。目前已有部分研究表明,PD-1/PD-L1抑制剂单药或联合化疗治疗可使胃癌及胃食管交界癌患者受益,预示着PD-1/PD-L1抑制剂联合手术及标准化治疗方案可能是提高胃癌患者治疗疗效的突破点。本文将对PD-1/PD-L1抑制剂治疗进展期胃癌的研究进展作一综述。     

PD-1/PD-L1 抑制剂治疗胃癌的研究进展

[摘要]免疫检查点为T 细胞提供抑制信号,造成肿瘤细胞免疫逃,为肿瘤治疗提供了全新的理念。程序性死亡受体（programmed cell death-1,PD-1）/程序性死亡受体配体-1（programmed death legend 1,PD-L1）成为最具发展前景的靶点,PD-1/PD-L1抗体在治疗黑色素瘤和非小细胞肺癌（NSCLC）中表现出显著的抗瘤效应和良好的安全性。在进展期胃癌患者外周血以及癌组织中PD-L1 均高表达,与多种病理特征存在一定正相关,往往是患者不良预后的预测指标。相关临床试验表明,应用PD-1/PD-L1抗体可使胃癌或胃食管交界癌患者受益,且无不可耐受副反应发生。而多种因素均与PD-1/PD-L1 表达相关,若调节这些因素的药物与PD-1/PD-L1 抑制剂联合应用,将有可能进一步提高胃癌的疗效。     

食管鳞癌PD-1/PD-L1分子生物学特点、与治疗和预后的相关性研究进展

PD-1(programmed cell death-1,程序性死亡受体1)与其配体PD-L1(programmed cell death-ligand 1,程序性死亡配体1) 是一对共刺激分子,对机体免疫反应起负性调节作用。阻断PD-1/PD-L1信号通路可以增强T细胞免疫功能,发挥抗肿瘤作用。目前有研究显示PD-1/PD-L1自身的分子生物学特性及在食管鳞状细胞癌（esophageal squamous cell carcinoma ,ESCC）组织中的表达水平可能与患者的预后有一定的相关性,本文就PD-1/PD-L1的生物结构、分子作用机制与ESCC和治疗、预后的相关性进行探讨。     

三阴性乳腺癌组织中LAG-3、PD-1、PD-L1的表达和TIL计数的临床意义

目的:探讨三阴性乳腺癌（triple-negative breast cancer,TNBC）组织中淋巴细胞激活基因-3(lymphocyte-activation gene-3,LAG-3)、程序性死亡受体-1(programmed death-1,PD-1)、程序性死亡受体-1配体(programmed death ligand-1,PD-L1)的表达和肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)计数的临床意义。方法:免疫组织化学法检测62例原发性TNBC组织和30例癌旁组织中LAG-3、PD-1、PD-L1的表达,苏木素-伊红法染色并计数TIL,分析四者与TNBC临床病理特征及预后的关系。结果:TNBC组织中LAG-3、PD-1和PD-L1表达显著高于癌旁组织（P＜0.01）;LAG-3表达与TNBC患者的淋巴结转移、Ki-67、PD-1、PD-L1表达和TIL计数有关（P＜0.05）;单因素分析显示,TNBC患者DFS与淋巴结转移、TNM分期、Ki-67、TIL、LAG-3+PD-1+、LAG-3+PD-L1+、LAG-3+TILlow有关（P＜0.05）;多因素分析显示,TNM分期、LAG-3+PD-L1+和TIL是TNBC患者预后的独立危险因素（P＜0.05）。结论:TNM分期、LAG-3+PD-L1+和TIL与TNBC患者不良预后有关,特别是LAG-3和PD-L1结合共表达,可为免疫检查点双重阻滞在TNBC患者的临床应用中提供更多的理论依据。     

PD-1/PD-L1在非小细胞肺癌中的临床研究进展

近年来,免疫治疗在癌症研究中取得了突飞猛进的发展。以程序性死亡受体-1（programmed cell death-1,PD-1）及其配体程序性死亡配体-1（programmed cell death-ligand 1,PD-L1）为靶点的免疫治疗药物在非小细胞肺癌（non-small cell lung cancer,NSCLC）的治疗中显示出了良好的疗效和耐受性,治疗前景值得期待。本文对PD-1/PD-L1治疗NSCLC的临床研究现状进行综述。      

晚期胃癌免疫检查点PD-1/PD-L1抑制剂联合治疗的研究进展

胃癌是最为常见的恶性肿瘤之一，在中国其发病率和死亡率均较高，大多数胃癌初诊即已为晚期，预后较差，目前治疗现状仍不理想。免疫逃逸是肿瘤发生发展的一主要机制，细胞程序性死亡受体-1（programmed death-1，PD-1）及细胞程序性死亡配体（programmed death-ligand 1，PD-L1）是导致免疫逃逸的重要分子，PD-1与PD-L1结合是肿瘤细胞免疫逃逸的重要发病机制之一，特异性阻断二者结合，可达到杀灭肿瘤细胞的目的。PD-1/PD-L1抑制剂可明显改善晚期胃癌患者预后，并且PD-1/PD-L1抑制剂联合化疗、靶向治疗、放疗等可进一步提高疗效。本文就PD-1/PD-L1抑制剂联合治疗在晚期胃癌中的治疗进展进行综述。      

免疫检查点在乳腺癌中的研究进展

免疫检查点对于维持自身免疫耐受、避免免疫系统对正常组织进行攻击发挥着至关重要的作用。肿瘤细胞能够利用免疫检查点通路的激活逃避免疫系统的识别。目前最重要的免疫检查点为细胞毒T淋巴细胞相关抗原-4（CTLA-4）、程序性死亡受体-1（PD-1）及程序性死亡受体配体-1（PD-L1）。肿瘤细胞PD-L1通过与活化的T细胞的PD-1结合,能够通过诱导T细胞的凋亡降低肿瘤免疫反应。免疫检查点抑制剂的应用能够延长肿瘤患者的生存时间。尽管目前对于免疫检查点认识有限,但免疫检查点抑制剂作为新的治疗方法有望改变乳腺癌的治疗模式。本篇综述将介绍乳腺癌中免疫检查点的研究进展。     

HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression

The NY-ESO1 gene is a cancer/testis antigen considered to be suitable target for the immunotherapy of human malignancies. Despite the identification of the epigenetical silencing of the NY-ESO1 gene in a large variety of tumors, the molecular mechanism involved in this phenomenon is not fully elucidated. In two non epithelial cancers (glioma and mesothelioma), we found that the epigenetic regulation of the NY-ESO1 gene requires the sequential recruitment of the HDAC1-mSin3a-NCOR, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a complexes. Thus, our data illustrate the orchestration of a sequential epigenetic mechanism including the histone deacetylation and methylation, and the DNA methylation processes.     

CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk factors for endometrial cancer susceptibility

BACKGROUND: In estrogen biosynthetic pathways, many enzymes are important for metabolism, detoxification, and bioavailability. Polymorphisms in these genes may have an effect on the enzymes' function. For example, higher expression and activation of biosynthetic enzymes and lower expression and activation of conjugation enzymes may lead to high toxicity or carcinogenesis. The authors hypothesized that single nucleotide polymorphisms (single nucleotide polymorphisms) of CYP1A1, CYP1A2, CYP1B1, CYP17, SULT1A1, SULT1E1, and SHBG genes may be risk factors for endometrial cancer. METHODS: DNA samples from 150 cases of endometrial cancer and healthy controls (n = 165) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the genotypic frequency of 13 different polymorphic loci on the CYP1A1 (m1, m2, m3, m4), CYP1A2 1F, CYP1B1 codon432, COMT codon158, CYP17, SULT1A1 (Arg213His, 14A/G, 85C/T in the 3' flanking region), SULT1E1-64G/A promoter region, and SHBG genes. Genotyping was validated by direct DNA sequencing. The authors also investigated the relation between expression of CYP1A1 in endometrial cancer tissues and genotypes of CYP1A1 m1. RESULTS: A decreased frequency of TC + CC genotype of the CYP1A1 m1 (T/C) polymorphism was observed in endometrial cancer patients compared with controls (OR = 0.42; 95% CI, 0.27-0.69). The T-A haplotype of CYP1A1 m1 and m2 was increased in endometrial cancer patients (P = .017). The frequency of CYP1A1 m1 T/C + C/C was higher in a high CYP1A1 expression group (P = .009). The authors also found that individuals carrying the variants of SULT1A1 codon213 and 2 single nucleotide polymorphisms in the 3' flanking region (14A/G and 85C/T) had an increased risk for endometrial cancer. The frequencies of G-A-C and A-G-T haplotypes of these 3 variants were higher in endometrial cancer patients (P < .0001; P = .0002). In addition, the frequency of combined genotypes (SULT1A1 213 GA + AA and CYP1A1 m1 TT) was higher in endometrial cancer patients. (OR, 4.58; 95% CI, 2.35-8.93). CONCLUSIONS: This is the first report on the combined association of CYP1A1 and SULT gene polymorphisms in endometrial cancer that suggests a decreased single nucleotide polymorphism of CYP1A1 and an increased single nucleotide polymorphism for SULT1A1 and SULT1E1 genes may be risk factors for endometrial cancer in Caucasians.     

CYP1A1.

CYP1A1 plays an important role in the metabolism of polycyclic hydrocarbons that occur in the environment and several studies suggest that the genetic polymorphism of the gene may play a role in the predisposition to cancer. In order to evaluate the function of CYP1A1 in vivo as a host factor determinant of environmentally-caused cancers in humans, additional investigations are needed involving not only molecular epidemiological approaches in different ethnic populations but also more direct approaches such as the use of gene-targeted mice as a model system.     

DNA切除修复交叉互补基因1、乳腺癌易感基因、核苷酸还原酶1与非小细胞肺癌

 阐述了近年来非小细胞肺癌（NSCLC）化疗敏感性与DNA 切除修复交叉互补基因1 （ERCC1）、乳腺癌易感基因（BRCA1）、核苷酸还原酶1（RRM1）基因表达关系的研究进展，分析3个基因对NSCLC个体化化疗潜在的指导意义     

Methoxyestrogens exert feedback inhibition on cytochrome P450 1A1 and 1B1

Cytochrome P450 1A1 (CYP1A1) and 1B1 (CYP1B1) catalyze the oxidative metabolism of 17 beta-estradiol (E2) to catechol estrogens (2-OHE2 and 4-OHE2) and estrogen quinones, which may lead to DNA damage. Catechol-O-methyltransferase catalyzes the methylation of catechol estrogens to methoxyestrogens (2-MeOE2, 2-OH-3-MeOE2, and 4-MeOE2), which simultaneously lowers the potential for DNA damage and increases the concentration of 2-MeOE2, an antiproliferative metabolite. In this study, we showed that CYP1A1 and CYP1B1 recognized as substrates both the parent hormone E2 and the methoxyestrogens. Using purified recombinant enzymes, we demonstrated that CYP1A1 and CYP1B1 O-demethylated the methoxyestrogens to catechol estrogens according to Michaelis-Menten kinetics. Both CYP1A1 and CYP1B1 demethylated 2-MeOE2 and 2-OH-3-MeOE2 to 2-OHE2, whereas CYP1B1 additionally demethylated 4-MeOE2 to 4-OHE2. Because the P450-mediated oxidation of E2 and the O-demethylation of methoxyestrogens both yielded identical catechol estrogens as products, we used deuterated E2 (E2-d4), unlabeled methoxyestrogens, and gas chromatography/mass spectrometry to examine both reactions simultaneously. Kinetic analysis revealed that methoxyestrogens acted as noncompetitive inhibitors of E2 oxidation with K(i) ranging from 27 to 153 micro M. For both enzymes, the order of inhibition by methoxyestrogens was 2-OH-3-MeOE2 > or = 2-MeOE2 > 4-MeOE2. Thus, methoxyestrogens exert feedback inhibition on CYP1A1- and CYP1B1-mediated oxidative estrogen metabolism, thereby reducing the potential for estrogen-induced DNA damage.     

Polymorphisms in CYP1B1, GSTM1, GSTT1 and GSTP1, and susceptibility to breast cancer

Polymorphisms in the cytochrome P450 1B1 (CYP1B1) and glutathione S-transferase (GST) drug metabolic enzymes, which are responsible for metabolic activation/detoxification of estrogen and environmental carcinogens, were analyzed for their association with breast cancer risk in 541 cases and 635 controls from a North Carolina population. Each polymorphism, altering the catalytic function of their respective enzymes, was analyzed in Caucasian and African-American women. As reported in previous studies, individual polymorphisms did not significantly impact breast cancer risk in either Caucasian or African-American women. However, African-American women exhibited a trend towards a protective effect when they had at least one CYP1B1 119S allele (OR=0.53; 95% CI=0.20-1.40) and increased risk for those women harboring at least one CYP1B1 432V allele (OR=5.52; 95% CI=0.50-61.37). Stratified analyses demonstrated significant interactions in younger (age < or =60) Caucasian women with the CYP1B1 119SS genotype (OR=3.09; 95% CI=1.22-7.84) and younger African-American women with the GSTT1 null genotype (OR=4.07; 95% CI=1.12-14.80). A notable trend was also found in Caucasian women with a history of smoking and at least one valine allele at GSTP1 114 (OR=2.12; 95% CI=1.02-4.41). In Caucasian women, the combined GSTP1 105IV/VV and CYP1B1 119AA genotypes resulted in a near 2-fold increase in risk (OR=1.96; 95% CI=1.04-3.72) and the three way combination of GSTP1 105IV/VV, CYP1B1 119AS/SS and GSTT1 null genotypes resulted in an almost 4-fold increase in risk (OR=3.97; 95% CI=1.27-12.40). These results suggest the importance of estrogen/carcinogen metabolic enzymes in the etiology of breast cancer, especially in women before the age of 60, as well as preventative measures such as smoking cessation.