非小细胞肺癌中肿瘤微环境细胞的表达特点及其与临床生存概率的相关性

目的:探究常见的肿瘤微环境细胞在非小细胞肺癌中的表达特点及其与临床生存概率的相关性.方法:我们首先从TCGA数据库中获取肺腺癌、肺鳞癌的基因表达数据和相应的临床信息;接着通过非参数检验分析了几种常见肿瘤微环境细胞在癌组织和癌旁肺组织之间的表达差异,以及细胞浸润程度与非小细胞肺癌生存概率之间的关系,并进行了多因素生存分析...     

Neoadjuvant immunotherapy for resectable non-small cell lung cancer

Lung cancer is the malignant tumor with the highest morbidity and mortality in the world. In recent ten years, with the emergence of new drugs and the optimization of treatment mode, the treatment of lung cancer is entering an era of precision and individualization. Neoadjuvant therapy can reduce tumor size, degrade tumor stage, kill circulating tumor cells and micrometastases in the body, afford operation possibility, and benefit the long-term survival of patients. However, the traditional neoadjuvant chemotherapy combined with surgical treatment seems to have entered the bottleneck period of efficacy and is difficult to achieve breakthrough progress. At the same time, the amazing efficacy of immunotherapy is gradually innovating the treatment mode of lung cancer. In recent years, the research data of immune checkpoint inhibitors in the treatment of non-small cell lung cancer (NSCLC) shows an explosive growth. Immunotherapy has been applied to the first-line treatment of advanced NSCLC. Therefore, some clinical trials have applied immunotherapy to neoadjuvant treatment of resectable NSCLC patients. In this paper, the efficacy, possible mechanisms, potential risks and existing problems of neoadjuvant immunotherapy for resectable NSCLC patients are reviewed, and the future development direction of neoadjuvant immunotherapy is discussed.     

人肺癌组织免疫缺陷鼠移植瘤模型的建立

背景与目的：目前提倡对肿瘤实行靶向药物个性化治疗,建立不同通路异常肿瘤的动物模型成为必需。本研究探讨人非小细胞肺癌手术标本免疫缺陷鼠皮下移植瘤模型的建立及建模的适宜条件和方法。方法：选取BALB／c裸小鼠、SCID小鼠及NOD／scid小鼠各16只,采用套管针四点左边两块、右边一块式接种法,16例患者中每例患者的肿瘤组织标本分别接种于每个鼠种的一只。观察不同种免疫缺陷鼠移植瘤成瘤率、成瘤潜伏时间、肿瘤体积倍增时间、自然病亡率及左右两边接种点的成瘤率和头尾部成瘤点处死时大于1cm的比率,并鉴别移植瘤形态结构与来源组织的一致性及鉴定移植瘤是否为上皮来源。结果：总成瘤率为75％,其中4个病例只有SCID小鼠成瘤．2个病例只有BALB／c裸小鼠成瘤,NOD／scid小鼠无一例单独成瘤。不同种免疫缺陷鼠移植瘤成瘤率、成瘤潜伏时间和肿瘤体积倍增时间及左右两边接种点的成瘤率差异无统计学意义。SCID小鼠成瘤率最高,为56．25％;NOD／scid小鼠自然病亡率为25％,BALB／c裸小鼠、SCID小鼠在观察期内无一例病亡;处死时头部成瘤点大于1cm的比率（56．52％）与尾部成瘤点大于1cm的比率（25％）相比差异有统计学意义（P=0．037）;所有移植瘤苏木精．伊红染色显示其形态结构均与来源组织一致,所有移植瘤角蛋白免疫组化均为阳性,显示移植瘤均为上皮来源。结论：四点两块套管针接种BALB／c裸小鼠和SCID小鼠各一只的方法能很好地建立非小细胞肺癌手术标本免疫缺陷鼠皮下移植瘤模型,头部移植瘤的生长速度明显快于尾部。     

Early immune pressure initiated by tissue-resident memory T cells sculpts tumor evolution in non-small cell lung cancer

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T lymphocytes related biomarkers for predicting immunotherapy efficacy in non-small cell lung cancer

The immune environment is a determinant of whether patients with cancer can benefit from immunotherapy. Immune checkpoint inhibitors (ICIs) have improved the prognosis of patients with different types of malignancies and have initiated a transformation in tumor therapy. However, some patients cannot achieve a long-term response and several patients even have no response to ICIs therapy. Thus, potential biomarkers that can effectively predict the efficacy of ICIs are essential for their clinical application and for the selection of patients. The accuracy of well-known biomarkers, such as expression of programmed cell death ligand 1 and tumor mutational burden, remains controversial. One of the critical factors for immune responses in the tumor microenvironment is tumor antigen-specific T cell. The density and distribution of tumor-infiltrating lymphocytes, T cells activation and T lymphocytes phenotypes in peripheral blood and serum cytokines have been observed in different types of solid cancer. Although the association with immunotherapy prognosis is in dispute, the prospect of T cell-related biomarkers is encouraged. The present review discusses whether these factors are associated with clinical outcomes of patients with non-small cell lung cancer. The association between several serum cytokines and ICIs therapy efficacy is also discussed.     

放疗联合免疫检查点抑制剂治疗非小细胞肺癌的研究进展

肺癌是世界范围发病率和死亡率最高的恶性肿瘤,非小细胞肺癌(non-small cell lung cancer,NSCLC)约占85％,其中30％～40％的患者确诊时为局部晚期,40％的患者为转移性肺癌.肺癌的治疗需要采用综合治疗手段,放疗作为传统治疗手段之一,在各期肺癌的治疗中发挥着重要作用.免疫检查点抑制剂(imm...     

三级淋巴结构在非小细胞肺癌中的研究进展

肺癌是世界上死亡率最高的恶性肿瘤,其中以非小细胞肺癌(non-small cell lung cancer,NSCLC)为著.肿瘤微环境是由肿瘤细胞、成纤维细胞、免疫细胞和肿瘤内脉管系统之间的相互作用形成的复杂网络.近年来有研究发现非小细胞肺癌中存在着三级淋巴结构(tertiary lymphoid structures,TLSs),有趣的是,这种三级淋巴结构有着与淋巴结类似的解剖结构.另外,三级淋巴结构中成熟DC/CD8+T细胞计数密度比值与非小细胞肺癌患者预后存在正相关性.本文将对NSCLC中有关TLSs的结构、功能及临床意义作简要概述.     

非小细胞肺癌循环肿瘤细胞检测进展

肺癌是世界范围内发病率最高的恶性肿瘤, 约有18%的癌症相关死亡与肺癌有关。循环肿瘤细胞(CTCs)的出现可看做是肿瘤细胞播散入血的直接体现, 而这正是导致非小细胞肺癌患者预后较差的最重要因素之一。检测外周血中循环肿瘤细胞有望成为诊断肺癌的辅助方法, 使肺癌患者得到最佳的个体化治疗。研究者们已尝试多种不同的方法从外周血中分离CTCs。虽然有关CTCs检测的研究众多, 但不同检测方法的敏感度、特异性及重复性限制了其临床意义, 本文就现有的各项技术进行综述。      

清热散结方对非小细胞肺癌化疗患者免疫功能的影响研究

目的 探讨清热散结方对非小细胞肺癌化疗患者免疫功能的影响.方法 回顾性分析98例非小细胞肺癌化疗患者的临床资料,按患者是否采用清热散结方进行治疗将其分为观察组(清热散结方治疗联合化疗)和对照组(单纯化疗),每组49例.统计和分析两组患者临床疗效、不良反应发生情况及外周血中T细胞亚群水平:CD3+T细胞、CD4+T细胞、CD8+T细胞、CD4+/CD8+T细胞比值及CD4+CD25+调节性T淋巴细胞比例变化.结果 治疗后,观察组与对照组的有效率和疾病控制率比较,差异无统计学意义(P﹥0.05).治疗后,观察组骨髓抑制、胃肠道反应的发生率均低于对照组,差异有统计学意义(P﹤0.05);脱发、周围神经毒性、肾功能损害的发生率均低于对照组,但差异无统计学意义(P﹥0.05).治疗后,观察组外周血中CD3+、CD4+、CD4+/CD8+水平均高于对照组,差异有统计学意义(P﹤0.05);观察组CD8+水平低于对照组,差异有统计学意义(P﹤0.05);观察组CD4+/CD25+水平低于对照组,但差异无统计学意义(P﹥0.05).结论 清热散结方对减轻非小细胞肺癌化疗患者骨髓抑制和胃肠道反应有积极作用,且对改善机体免疫功能有促进作用.     

非小细胞肺癌中EGFR和K-ras基因突变检测

目的:探讨不同类型非小细胞肺癌的EGFR和K-ras基因突变情况及其与肺癌相关临床病理特征的关系。方法:用厦门艾德ADxARMS试剂盒进行98例非小细胞肺癌患者肿瘤组织中EGFR（18,19,20,21外显子）基因和K-ras（12,13,61密码子）基因突变的检测。所有患者均未接受过吉非替尼的治疗。结果:98例样本中31例发生了EGFR基因突变,突变率为31.6%（31/98）,其中15例为19外显子缺失,13例为21 L858R外显子点突变,3例为20外显子突变,1例为18外显子突变。其中1例既有19外显子缺失突变,又有20外显子突变。腺癌中EGFR基因突变率较鳞癌、腺鳞癌、大细胞癌高。女性患者EGFR基因突变率较男性高。不吸烟患者EGFR基因突变率较吸烟患者高。低分化腺癌患者EGFR基因突变率较中、高分化患者高。21例发生了K-ras基因突变（21.4%）,其中12、13、61密码子均发现突变。突变率腺癌较鳞癌、腺鳞癌、大细胞癌高,与是否吸烟、患者性别、分化程度均无相关性。结论:非小细胞肺癌患者EGFR基因突变检出率较高,K-ras基因突变率较低,且两者不存在同时突变,EGFR基因突变与肺癌组织学类型、分化程度、性别等相关。K-ras基因突变与组织学类型相关。     

肿瘤抗原致敏树突状细胞疫苗联合热疗治疗晚期非小细胞肺癌的临床观察

目的: 探讨树突状细胞疫苗联合热疗治疗晚期非小细胞肺癌的安全性和临床疗效。方法： 14例晚期非小细胞肺癌患者入组，均符合研究的纳入及排除标准，并签署知情同意书；患者单采外周血单核细胞体外培育成树突状细胞，将抗原致敏制备成的树突状细胞疫苗回输患者，回输前1 d使用     

免疫治疗联合放疗治疗晚期非小细胞肺癌的进展

晚期非小细胞肺癌（non-small cell lung cancer,NSCLC）患者手术、放疗、化疗治疗效果欠佳,预后较差。近年来针对NSCLC免疫治疗联合放疗的研究越来越多,可取得较好的肿瘤控制效果。本文就NSCLC免疫治疗联合放射治疗的相关进展进行综述。     

Expression of methylation-related genes is associated with overall survival in patients with non-small cell lung cancer

The abnormality of DNA methylation is involved in tumour progression, and thus has a modulating effect on clinical outcome of cancer patients. In this study, we measured the mRNA expression levels of three methylation-regulating genes (DNMT1, DNMT3b, and MBD2) in 148 tumour samples from patients with non-small cell lung cancer (NSCLC) using quantitative real-time polymerase chain reaction and then determined their prognostic values. Our data showed that the high level of DNMT1 expression was significantly associated with an increased risk of death in all NSCLC patients (hazard ratio (HR), 1.74; 95% confidence interval (95% CI), 1.04-2.90). However, the high level of DNMT3b expression was significantly associated with poor prognosis only in young patients (<65 years). The high level of MBD2 expression had a significantly reduced risk for death only in male patients and in squamous cell lung carcinoma (SQLC) patients. All three combination groups with DNMT1 and DNMT3b, DNMT1 and MBD2 or DNMT3b and MBD2 revealed significant combined effects in male patients and SQLC patients. Our results suggest that DNMT1, DNMT3b, and MBD2 may play important roles in modulating NSCLC patient survival and thus be useful for identifying NSCLC patients who would benefit most from aggressive therapy.     

Immunological effect of tyrosine kinase inhibitors on the tumor immune environment in non-small cell lung cancer

Acquired resistance to tyrosine kinase inhibitors (TKIs) limits the duration of antitumor effects and impairs the survival of patients with oncogene-driven non-small cell lung cancer (NSCLC). At present, little is known about the immunomodulatory ability of TKIs during the entire treatment period, including the drug-sensitive and drug-resistant periods. The present review aimed to comprehensively explore the dynamic changes in the tumor microenvironment (TME) during TKI treatment in NSCLC. Previous clinical and preclinical studies from medical and health databases related to NSCLC are reviewed. During the response period, cytotoxic immune cells accumulate in the TME and contribute to the formation of an inflammatory microenvironment. During the resistance period, the number of immunosuppressive cells increases, as does the expression of immune checkpoint proteins, which are critical mechanisms for tumor progression. The combination of targeted therapy and immunotherapy has been explored in multiple studies, and preliminary data showed controversial results. Extensive studies are needed to confirm the criteria of the selected patient subgroups and the toxicity profiles of EGFR TKIs and immune checkpoint inhibitors (ICIs). At present, the reagents targeting other immune cells, cytokines and related pathways remain underexplored compared with the revolutionary effect of ICIs in lung cancer. In the future, the precisely selected regimens for combination treatment should be further investigated in carefully designed xenograft models and clinical trials.     

非小细胞肺癌血清miR-191的表达及意义

目的:探讨血清miR-191对非小细胞肺癌（non-small cell lung cancer,NSCLC）的诊断价值及临床特征。方法:采用实时荧光定量PCR技术检测65例非小细胞肺癌患者血清和65例健康人血清中miR-191的表达量,分析血清miR-191的表达与非小细胞肺癌临床病理参数的关系,通过绘制ROC曲线分析其诊断非小细胞肺癌的价值。结果:非小细胞肺癌患者血清miR-191相对表达水平高于正常对照组(P＜0.05),其表达与临床分期、病理类型及淋巴结转移显著相关（P＜0.05）,而与性别、年龄及吸烟史无相关性(P＞0.05);miR-191的ROC曲线下面积AUC=0.951,其诊断非小细胞肺癌的灵敏度为87.3%,特异度为92.3%。结论:血清miR-191测定的诊断性能较高,有望作为诊断非小细胞肺癌的潜在分子标志物。     

晚期非小细胞肺癌的治疗选择

肺癌是世界范围内癌症相关死亡的首要病因。近年来,非小细胞肺癌（non-small cell lung cancer ,NSCLC ）的治疗取得了巨大进步。人们对肺癌病理组织学认识不断深入,根据病理组织分型制订了相应的化疗方案。此外随着对分子生物学研究的发展,人们发现了在肿瘤发生发展过程中的驱动性基因突变,并以此研发了一系列针对不同分子亚型的靶向药物。本文将结合近期一系列临床研究结果,对晚期NSCLC 的临床治疗策略进行论述。     

Programmed cell death ligand-1 (PD-L1) expression combined with CD8 tumor infiltrating lymphocytes density in non-small cell lung cancer patients

Cancer immunotherapy targeting programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) pathway has shown promising results in treatment of non-small cell lung cancer (NSCLC) patients. T cells play a major role in tumor-associated immune response. This study aimed to investigate PD-L1 expression alone and combined with CD8 tumor infiltrating lymphocytes (TILs) density in relation to clinicopathologic parameters and survival in NSCLC patients. Immunohistochemical analysis was used to evaluate PD-L1 expression and CD8 TILs density in 55 NSCLC patients. PD-L1 immunopositivity was detected in 36 (65.5%) of NSCLC cases. PD-L1 expression was significantly related to high tumor grade (p value?=?0.038) and low CD8 TILs density (p value?=?0.004), whereas no significant relations were detected between PD-L1 expression and tumor stage (p value?=?0.121), overall survival (OS) (p value?=?0.428) and progression-free survival (PFS) (p value?=?0.439). Among PD-L1/CD8 TILs density groups, PD-L1⁺/CD8^Low group was significantly associated with high tumor grade compared to PD-L1^?/CD8^high group (pairwise p?=?0.016). PD-L1⁺/CD8^Low group was significantly related to advanced tumor stage compared to PD-L1⁺/CD8^high and PD-L1^?/CD8^Low groups (pairwise p?=?0.001 and 0.013 respectively). PD-L1^?/CD8^high group exhibited the best OS and PFS whereas PD-L1⁺/CD8^low group had the poorest OS and PFS (p value?=?0.032 and 0.001 respectively). Assessment of PD-L1 combined with CD8 TILs density, instead of PD-L1 alone, suggested important prognostic relevance in NSCLC patients.     

BIRC5基因在非小细胞肺癌中的表达及与免疫细胞浸润和预后的关系

目的:通过生物信息学方法分析杆状病毒凋亡抑制蛋白5(baculoviral inhibitor of apoptosis repeat-containing protein 5,BIRC5)基因在非小细胞肺癌(non-small cell lung cancer,NSCLC)与正常组织中的表达差异,并分析其与NSCLC...     

NSCLC患者外周血淋巴细胞多药耐药基因的表达与长春瑞滨化疗疗效的相关性研究

目的：检测多药耐药基因（MDR-1）在非小细胞肺癌患者外周血淋巴细胞中的表达，探讨MDR-1的表达与肺癌的病理类型及分期的关系及与长春瑞滨联合铂类化疗疗效之间的关系。方法：采用逆转录聚合酶链反应（RT—PCR）技术检测46例非小细胞肺癌患者外周血中MDR-1的表达水平，并与30例健康对照组进行比较。非小细胞肺癌患者均采用NP方案治疗，2个治疗周期后评价疗效。结果：非小细胞肺癌组外周血淋巴细胞MDR-1阳性检出率36．95％（17／46），其中腺癌9例阳性，鳞癌7例阳性，腺鳞癌1例阳性，Ⅰ期1例阳性，Ⅱ期3例阳性，Ⅲ期7例阳性，Ⅳ期6例阳性，而健康对照组仅1例阳性。MDR-1表达阳性的非小细胞肺癌患者应用长春瑞滨联合铂类化疗的有效率明显低于MDR-1表达阴性者，差异具有统计学意义。结论：非小细胞肺癌患者外周血淋巴细胞MDR-1表达水平较高，与肺癌的病理类型及分期无关；与长春瑞滨联合铂类化疗的临床疗效具有一定的相关性，临床上可根据MDR—1表达情况，制定个体化的化疗方案。