PD-1 PD-L1单抗在复发转移性鼻咽癌中的研究进展

鼻咽癌患者经放疗及同步辅助化疗后，临床转归有所改善，但肿瘤复发及远处转移仍为一项难题。近些年，免疫检查点抑制剂的发现为肿瘤的免疫治疗提供了新的选择。其中，程序性细胞死亡受体1（programmed cell death protein-1，PD-1）/程序性死亡受体配体1（programmed cell death 1-ligand，PD-L1）单抗受到广泛关注且已应用于临床治疗。本文就帕博利珠单抗、纳武利尤单抗、卡瑞利珠单抗和特瑞普利单抗等PD-1/PD-L1单抗在复发/转移性鼻咽癌中的研究进展进行综述。      

抗PD-1/PD-L1疗法致免疫相关不良反应机制及预测标志物的研究进展

抗程序性细胞死亡受体-1(programmed cell death protein-1,PD-1)和抗程序性死亡受体配体-1(programmed cell death ligand-1,PD-L1)是目前广泛使用的免疫检查点抑制剂,在肿瘤免疫治疗方面取得了巨大的成就,但同时也导致免疫相关不良反应(immune-related adverse events, irAEs),严重者甚至会导致患者死亡。因此,明确irAEs的发生机制,提早预测irAEs非常重要。本文由细胞、免疫系统、个体水平层面对抗PD-1/PD-L1疗法致irAEs的发生机制进行了总结,并从一般临床特征、免疫细胞因素、细胞因子相关、基因表达结果等方面汇总了irAEs的预测指标。     

PD-1/PD-L1抑制剂的剂量选择与优化

摘 要：肿瘤免疫治疗中，以程序性死亡受体1（programmed cell death protein 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检查点单抗阻断治疗已逐渐成为肿瘤治疗领域的焦点。合理用药是使患者达到有效临床获益的重要环节，其中用药剂量准确是合理用药的关键。因此，充分了解PD-1/PD-L1抑制剂的药代动力学、药效学特点以及由此衍生的剂量选择和剂量优化方案对消除用药疑虑、增强用药依从性，从而实现规范化用药具有重要的临床意义。全文就PD-1/PD-L1抑制剂的剂量优化历程和临床应用进行综述，以期为PD-1/PD-L1抑制剂的临床规范使用提供参考。     

基于PD-1/PD-L1 抑制剂的肺癌免疫治疗预测标志物的研究进展

[摘要] 近年来,免疫检查点抑制剂在肺癌治疗中取得突破性进展,正迅速改变着肺癌的治疗模式,也标志着免疫治疗2.0 时代的到来。新的肿瘤治疗模式对精准医学提出更高要求,对程序性死亡受体1（programmed death 1, PD-1）/程序性死亡配体1（programmed death ligand 1, PD-L1）抑制剂预后生物标志物也在不断地探索之中,主要包括以下几个方面：PD-L1 表达水平、肿瘤基因组异质性与肿瘤新抗原、T细胞特点、肿瘤微环境以及机体整体状态等。本文将针对目前PD-1/PD-L1 抑制剂在肺癌免疫治疗中的潜在生物标志物最新临床研究进展及其研究前景进行综述。     

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。      

循环外泌体PD-L1表达水平与PD-1/PD-L1抑制剂治疗恶性肿瘤疗效的相关性研究现状

外泌体作为具有生物学功能的小囊泡，是近年肿瘤研究领域关注的热点。研究发现，肿瘤细胞分泌的外泌体表达的程序性死亡受体配体1(programmed death ligand 1，PD-L1)，可在肿瘤患者外周血液中检测到，可能参与并抑制机体免疫反应。近年来，一些研究发现，外泌体PD-L1可能影响程序性死亡受体1（programmed death 1，PD-1）/PD-L1抑制剂的抑制效应。反之，亦然。应用PD-1/PD-L1抑制剂治疗，可影响外泌体PD-L1的表达水平。二者有怎样的联系和相关性？本文就循环外泌体PD-L1在不同肿瘤免疫反应及抗PD-1/PD-L1免疫治疗中的研究进展作一综述。     

PD-1/PD-L1免疫抑制剂在非小细胞肺癌免疫治疗中的研究进展

摘 要：近年来免疫检查点领域研究进展迅速,众多新药相继出现,其中包括程序性细胞死亡蛋白1（programmed cell death protein 1,PD-1）单抗Pembrolizumab和Nivolumab,程序性细胞死亡蛋白配体1（programmed cell death protein ligand 1,PD-L1）单抗Atezolizumab。免疫检查点PD-1/PD-L1抑制剂给EGFR突变阳性非小细胞肺癌患者带来更多的生存获益,正逐渐改变国内外EGFR突变阳性晚期非小细胞肺癌的治疗模式。全文对PD-1/PD-L1为靶向的肿瘤免疫治疗在晚期EGFR突变阳性非小细胞肺癌患者治疗中的研究进展进行综述。     

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。     

外泌体PD-L1在肿瘤免疫治疗中的研究进展

近年来,肿瘤免疫治疗取得了重大的进步,目前以程序性细胞死亡蛋白1（programmed cell death protein-1,PD-1）/程序性细胞死亡蛋白-配体1（programmed cell death protein-ligand 1,PD-L1）抑制剂为代表的新型免疫治疗临床应用如火如荼进行中,但在PD-1/PD-L1抑制剂应用中,不同患者和不同肿瘤类型之间疗效差异显著。现有研究发现外泌体PD-L1能解释这种疗效差异,主要机制是外泌体PD-L1可代替细胞PD-L1,产生抑制T细胞活化作用,同时,还可将功能性PD-L1转移到其他细胞,产生免疫抵抗或免疫耐受,影响PD-1/PD-L1抑制剂治疗结局。本文将对外泌体PD-L1与肿瘤免疫治疗的关系进行简要介绍。     

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。      

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.

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.     

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.     

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.     

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     

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.     

CYP1A1 and GSTM1 polymorphisms affect urinary 1-hydroxypyrene levels after PAH exposure

Certain human biotransformation enzymes have been implicated in the formation and scavenging of the ultimate reactive metabolites, the diolepoxides, from polycyclic aromatic hydrocarbons (PAHs). In the present study, performed on aluminum smelter workers, we have analyzed airborne PAH, the pyrene metabolite 1-hydroxypyrene (1-OHP) in urine, and genotypes for biotransformation enzymes involved in PAH metabolism. The aim was to evaluate the correlation between external exposure and biomarkers of exposure and to investigate to what extent genetic polymorphism in metabolic enzymes can explain interindividual variation in urinary 1-OHP levels. DNA was prepared from blood samples from 98 potroom workers and 55 controls and altogether eight polymorphisms in the CYP1A1, mEH, GSTM1, GSTP1 and GSTT1 genes were analyzed. The 1-OHP excretion was found to correlate significantly (P 100-fold) and univariate and multivariate regression analyses were used to find the variables that could determine differences in excretion. The variation could, to some degree, be explained by differences in exposure to airborne particulate-associated PAHs, the use of personal respiratory protection devices, smoking habits and genetic polymorphisms in the cytochrome P450 1A1, GSTM1 and GSTT1 enzymes. The part of the variance that could be explained by differences in biotransformation genotypes seemed to be of the same order of magnitude as the variance explained by differences in exposure. In the control group as well as in the occupationally exposed group, the highest 1-OHP levels were observed in individuals carrying the CYP1A1 Ile/Val genotype who were also of the GSTM1 null genotype. The results show that urinary 1-OHP is a sensitive indicator of recent human exposure to PAHs and that it may also to some extent reflect the interindividual variation in susceptibility to PAHs.