胰腺癌免疫治疗的挑战与前景

胰腺癌是一种恶性程度极高的消化系统恶性肿瘤,预后极差.有报告称胰腺癌当前已超过乳腺癌成为美国第三位的癌症死亡病因.由于胰腺癌早期诊断率较低,大多数患者在确诊时已失去手术的机会,而且各种现有的治疗策略(如放疗、化疗,靶向治疗等)尚无法显著提高其生存率.大量证据表明导致胰腺癌高致死性的一个重要原因是由免疫抑制微环境, T细胞浸润低和基因突变负荷低等因素驱动而获得的肿瘤免疫特权.近年来,肿瘤免疫治疗已成为肿瘤学领域的热点,在胰腺癌的治疗方面也取得了显著的进展.目前,各种新的免疫治疗策略如免疫检查点阻断剂,过继性细胞疗法和肿瘤疫苗等已进入临床或临床前期阶段,都有希望成为提高胰腺癌患者救治率的新治疗手段.因此,本文简要概括近些年正在研究且有希望的胰腺癌免疫疗法的最新进展,以及当前所面临的挑战与前景,为以后研发新的高效的胰肿瘤免疫治疗手段开阔视野.     

胰腺癌肿瘤微环境的机制及靶向治疗

胰腺癌肿瘤微环境是一个包含胰腺星状细胞、癌相关成纤维细胞、免疫细胞和细胞外基质的过度纤维化的致密基质环境，不仅为肿瘤创造了促进其生长和侵袭的环境，并使其对化疗和其他抗肿瘤药物产生耐受抵抗。基质中密集纤维化反应和肿瘤在免疫环境中的改变被认为是目前胰腺癌治疗失败的主要原因。本文回顾了近年来胰腺癌肿瘤微环境相关研究进展，对其组成成分和致病机制以及针对基质和免疫的靶向治疗作一综述，分析肿瘤微环境对胰腺癌发生进展的重要性及其在靶向治疗方面的影响。     

胰腺癌基因治疗的研究现状

胰腺癌的基因治疗作为一种新的治疗手段,近年来备受关注,其很多研究已进入临床阶段.胰腺癌基因治疗的研究主要包括:反义基因治疗、自杀基因治疗、免疫基因治疗及肿瘤裂解病毒基因治疗等.本文就近期胰腺癌的基因治疗研究成果与存在的问题作一综述.     

树突状细胞胰腺癌免疫治疗新进展

胰腺癌早期诊断困难.临床常规治疗方法效果均欠佳[1].通过调节肿瘤抗原的递呈以增强抗肿瘤免疫应答是目前肿瘤免疫治疗的蕈要策略之一.树突状细胞(DC)作为功能强大的抗原递呈细胞和免疫反应启动者,与机体免疫状态密切相关,在胰腺癌免疫治疗中已显示出其独特的应用价值.     

系统免疫炎症指数与胰腺癌预后的相关性

炎症广泛参与肿瘤的发生与发展,对胰腺癌进展起着至关重要的作用。同时炎性细胞是构成肿瘤微环境的一部分,在促进肿瘤细胞的增殖和侵袭性转移起着关键作用。近年来,越来越多的研究探讨以中性粒细胞、淋巴细胞和血小板为基础的系统免疫炎症指数与恶性肿瘤患者预后的关系,其中也包括对胰腺癌的研究。本文通过阐述系统免疫炎症指数与胰腺癌患者预后的关系,为制订适当的胰腺癌治疗策略提供参考。     

基于生物信息学分析PDE2A基因在消化系统肿瘤预后及免疫浸润的临床意义

背景 消化系统肿瘤是最常见的恶性肿瘤之一,然而其预后仍不好.探索潜在生物标志物是肿瘤研究的重要方向.我们拟利用生物信息学方法探索消化系统的潜在标志物.目的 探究在消化系统肿瘤中PDE2A表达与免疫浸润相关性,探索PDE2A在消化系统肿瘤中的预后价值.方法 通过HPA、TIMER和UALCAN数据库分析PDE2A在不同消化系统肿瘤中的mRNA及蛋白表达,利用GEPIA数据库探索PDE2A在不同消化系统肿瘤患者预后的影响.通过TIMER数据库探索PDE2A表达与不同消化系统肿瘤免疫浸润相关性.利用cB ioP ortal数据库分析PDE2A在不同消化系统肿瘤的遗传突变信息.通过STRING数据库探索PDE2A的潜在蛋白相互作用网络.结果 PDE2A基因mRNA和蛋白在肝癌、胃癌、胰腺癌、结肠癌和食管癌组织中表达低于正常癌旁组织.PDE2A高表达的肝癌和胰腺癌患者较PDE2A低表达的患者预后良好. PDE2A表达与肝癌、胃癌、胰腺癌、结肠癌和食管癌不同免疫细胞如CD4+T淋巴细胞、CD8+T淋巴细胞、B细胞、巨噬细胞和中性粒细胞呈正相关或负相关. PDE2A基因在胃癌、胰腺癌、结肠癌及食管癌中存在错义突变等遗传改变.结论 PDE2A表达与消化系统肿瘤免疫浸润有关. PDE2A高表达的肝癌和胰腺癌患者预后良好. PDE2A基因可能为潜在的消化系统肿瘤免疫治疗靶点和预后标志物.     

胰腺癌缺氧微环境的生物学作用

癌细胞生长迅速及中心血供不足导致的缺氧是肿瘤微环境特性之一,在胰腺癌中尤为突出。越来越多的研究显示,缺氧与胰腺癌的血管新生、代谢重建、肿瘤增殖及早期浸润转移密切相关,并通过分泌多种活性因子介导肿瘤免疫逃避。此外,耐药作为胰腺癌治愈率低的关键因素,也与缺氧相关。缺氧与胰腺癌的发生发展密不可分,并依赖于缺氧诱导因子发挥作用。对缺氧微环境与胰腺癌的关系进行了总结,并探讨相关信号通路激活与分子机制,以期为胰腺癌缺氧微环境靶向治疗提供线索。     

胰腺癌免疫治疗研究现状

胰腺癌是一种临床预后极差的消化道恶性肿瘤,根治性手术是胰腺癌患者首选治疗方案,但大多数患者确诊时已无根治性手术治疗机会.目前,已开展多项以免疫检查点抑制剂、肿瘤疫苗、过继细胞疗法等手段为主的胰腺癌免疫治疗研究,有望成为胰腺癌治疗的新策略,最终达到提高胰腺癌患者整体预后的目的.本文简要概括胰腺癌免疫治疗研究现状,并分析胰腺癌免疫治疗研究的未来趋势.     

酪氨酸激酶受体RON在胰腺癌中的表达及意义

目的:研究酪氨酸激酶RON(recepteur d'origine nantais)在胰腺癌组织中的表达及其意义.方法:收集胰腺癌组织及相关癌旁组织31例.正常胰腺组织8例,采用免疫组织化学技术检测组织中RON的表达.结果:RON在正常胰腺组织、癌旁组织、胰腺癌组织中均见阳性表达,胰腺癌及癌旁中的表达强度高于正常胰腺组织,胰腺癌RON的表达强度强于癌旁组织(P＜0.05).RON表达与患者年龄、肿瘤大小、组织学类型和肿瘤部位等均无关,与胰腺癌临床分期、分化程度及淋巴结转移相关(P＜0.05).结论:RON表达量的增多与胰腺癌的发生、发展有关.     

整合素连接激酶在胰腺癌中的表达及意义

目的 探讨整合素连接激酶(intergrin linked kinase,ILK)在胰腺癌组织中的表达及其临床意义.方法 采用免疫组织化学法和Western blotting法检测ILK在60例胰腺癌和32例癌旁正常胰腺组织中的表达,并分析其与临床病理参数的关系.结果 免疫组化结果显示,ILK蛋白在胰腺癌细胞胞质内和胞膜上以及间质中均有表达,其阳性表达率为65.0%(39/60),显著高于正常胰腺组织的18.8%(6/32,P＜0.05).Western blotting结果显示,ILK在胰腺癌组织中的相对表达量为303933±195116,显著高于正常胰腺组织的144613±30074(P＜0.05).在胰腺癌组织中,ILK表达与肿瘤的临床分期和淋巴结转移有关(P＜0.05),而与肿瘤分化程度无关.结论 ILK在胰腺癌组织高表达,并与肿瘤的恶性程度相关.     

肿瘤生物化疗的研究进展

近年来随着科学技术的发展,恶性肿瘤的早期诊断率有所提高,但其治疗仍是一个难题.传统的手术、化疗、放疗并不能从根本上消灭肿瘤,大部分肿瘤患者的长期生存率较低.在生物和免疫学技术飞速发展的推动下,生物治疗的出现为人们对抗肿瘤带来了新的希望.生物治疗与化疗的结合--生物化疗更是为恶性肿瘤的治疗带来了新的理念,并且得到了较好的发展.     

Kupfer-type immunological synapse characteristics do not predict anti-brain tumor cytolytic T-cell function in vivo

To analyze the in vivo structure of antigen-specific immunological synapses during an effective immune response, we established brain tumors expressing the surrogate tumor antigen ovalbumin and labeled antigen-specific anti-glioma T cells using specific tetramers. Using these techniques, we determined that a significant number of antigen-specific T cells were localized to the brain tumor and surrounding brain tissue and a large percentage could be induced to express IFNγ when exposed to the specific ovalbumin-derived peptide epitope SIINFEKL. Detailed morphological analysis of T cells immunoreactive for tetramers in direct physical contact with tumor cells expressing ovalbumin indicated that the interface between T cells and target tumor cells displayed various morphologies, including Kupfer-type immunological synapses. Quantitative analysis of adjacent confocal optical sections was performed to determine if the higher frequency of antigen-specific antiglioma T cells present in animals that developed an effective antitumor immune response could be correlated with a specific immunological synaptic morphology. Detailed in vivo quantitative analysis failed to detect an increased proportion of immunological synapses displaying the characteristic Kupfer-type morphology in animals mounting a strong and effective antitumor immune response as compared with those experiencing a clinically ineffective response. We conclude that an effective cytolytic immune response is not dependent on an increased frequency of Kupfer-type immunological synapses between T cells and tumor cells.     

Optimal production of murine monoclonal antibodies in ascites of syngeneic mice by a single whole body irradiation

Hybridoma cells injected intraperitoneally into mice induce formation of ascites tumors producing ascites fluid with high levels of monoclonal antibodies. Several parameters affect the growth of the immunoglobulin-producing tumors in vivo. In the present study the average ascites tumor formation rate of 10 different hybridomas could be increased from 32% (n = 338 mice) to 77% (n = 112 mice) by only one whole body irradiation of paraffin-pretreated-Balb/c mice. Production of monoclonal antibodies was better in males because significantly (p less than 0.01) increased volume of ascites fluid. From the increased tumor formation rate in irradiated mice it is suggested that in non-irradiated recipients the tumor growth rate was lowered by immunological reactions against hybridoma cells provoked by cell surface neoantigens revealed by cell fusion and/or tumor-associated antigens of the myeloma parent cells as well as by altered antigen pattern caused by possible mutations in the myeloma cell line and/or Balb/c/K strain.     

In vivo assessment of angioarchitecture and microcirculation in experimental liver cancer: a new model in rats

The rising incidence of unresectable hepatocellular malignancies remains a therapeutic challenge. Little is known about the mechanisms of angiogenesis and immunological aspects of liver tumor vessels. The aim of this study was to investigate hepatic and tumor microcirculation and leukocyte–endothelium interaction by means of intravital microscopy in a rat model of hepatocellular carcinoma. Off-line analysis showed that the angioarchitecture as well as blood flow velocity in liver cancer is heterogeneous. The leukocyte–endothelium interaction is significantly reduced compared to normal liver tissue. The data suggest that the main mechanism is a reduced expression of adhesion molecules demonstrating an effective immune escape mechanism of this tumor. The model represents a useful experimental tool to explore angiogenesis inhibition or immunological therapeutic strategies in experimental liver cancer.     

肿瘤突变负荷对非小细胞肺癌免疫治疗疗效的预测价值

随着人们对肿瘤免疫研究的深入,免疫检查点抑制剂为代表的免疫治疗在临床试验及实践中获得了满意疗效,但客观缓解率较低,其疗效暂不明确。目前有效预测免疫治疗疗效的标志物一直没有定论。多项临床试验表明肿瘤突变负荷(TMB)与T淋巴细胞识别抗原及免疫疗效呈正相关,可用于预测免疫检查点抑制剂的疗效,但TMB预测免疫治疗疗效尚存在一定的局限性。为此,本文综述了TMB对非小细胞肺癌(NSCLC)免疫治疗疗效的预测价值及目前应用的局限性。     

ACCELERATION BY THYMOSIN OF THE DEVELOPMENT OF RESISTANCE TO MURINE SARCOMA VIRUS-INDUCED TUMOR IN MICE

The development of resistance to progressive tumor growth and the effect of a thymic extract upon this developmental process were examined in CBA/Wh mice. Inoculating mice of various ages with murine sarcoma virus (Moloney) permitted the assessment of the period of time postnatally at which the animals developed a threshold level of resistance to progressive tumor growth. Resistance in CBA/Wh mice, at the virus dose used, was first detected at approximately two weeks of age and was completely developed at five weeks.Thymosin, a soluble calf thymic fraction, when administered to neonatal mice beginning on the second day of life, significantly accelerated the rate of development of resistance to progressive tumor growth. The data suggest a humoral role for the thymus in the development of tumor immunity, and that the normal development of cell-mediated immunological competence can be accelerated through the use of thymus-derived extracts.     

免疫记忆:一把双刃剑

免疫系统与抗原接触,产生对其初次的特异性应答;当免疫系统再次与该抗原接触时,通常会产生再次应答;这一现象称之为免疫的记忆性。在抗感染免疫方面,免疫记忆现象的存在可以防止同一疾病的再次发生,对人体产生保护作用,这也是预防接种的免疫基础。但免疫记忆对人体不只有保护作用,在某些情况下也会对人体产生负面影响。本文就免疫记忆现象在抗感染免疫,肿瘤免疫,移植免疫,以及自身免疫性疾病和变态反应性疾病等方面对人体的正反两方面作用进行综述。深入研究其负面作用,可能为免疫相关性疾病的发生,发展及治疗研究展开一个全新的视界。     

Molecular weights of adrenocorticotropic hormone in extracts of anterior and intermediate-posterior lobes of mouse pituitary.

The molecular weight of the adrenocorticotropic hormone (ACTH) activity in extracts of the separated anterior and intermediate-posterior lobes of the mouse pituitary was determined by gel filtration in guanidine-HCl. Following dilution or removal of the guanidine-HCl, ACTH activity was quantitated by both radioimmunoassay and bioassay. Extracts of the intermediate-posterior lobe contain approximately a tenth as much ACTH activity as extracts of the anterior lobe. In extracts of both the anterior and the intermediate-posterior lobes, about half of the immunological ACTH activity is similar in size to porcine ACTH (molecular weight 4000--5500). Two higher molecular weight forms of ACTH account for the remainder of the ACTH activity. About 40% of the immunological ACTH activity in anterior lobe extracts has a molecular weight of 6500--9000. Extracts of both the anterior lobe and the intermediate-posterior lobe contain ACTH activity with a molecular weight of 20,000--30,000. While this 20,000--30,000 molecular weight ACTH accounts for only 5% of the immunological ACTH activity in the anterior lobe extracts, it accounts for half of the immunological ACTH activity in extracts of the intermediate-posterior lobe. Extracts of an ACTH-secreting mouse pituitary tumor cell line (AtT-20/D-16v) contain the same three molecular weight forms of ACTH. Each of the three molecular weight forms of ACTH has a characteristic ratio of biological ACTH activity to immunological ACTH activity, independent of the source of the material (anterior lobe, intermediate-posterior lobe, or mouse pituitary tumor cell line).     

A case of intractable hemoptysis due to malignant hemangioendothelioma]

A 65-year-old man who died of respiratory failure due to malignant hemangioendothelioma is reported. He was admitted to our hospital because of intractable hemoptysis. Chest roentgenogram revealed multiple patchy shadows in both lungs, but we could not make a diagnosis by usual clinical examinations including transbronchial lung biopsy. Since the patient's condition became critical, oxygen therapy, anticoagulants and antibiotics were started. In addition, corticosteroid therapy and double filtration plasmapheresis were performed since immunological disorder was suspected because of positive immunological examinations such as antinuclear antibodies and an increase in circulatory immune complexes. There was little response to the treatments and the patient finally died of respiratory failure. At autopsy, multiple tumor nodules were found throughout the lungs and the liver. Metastasis to mediastinal lymph nodes was also discovered. These findings made it impossible to confirm the primary lesion. Microscopy showed proliferation of anastomosing capillaries encasing tumor cells of unknown origin. Silver staining demonstrated capillaries encompassing the atypical cells, suggesting a vascular origin of the tumor. Furthermore, factor VIII related-antigen in the tumor cells was confirmed by the peroxidase-antiperoxidase (PAP) method. The final diagnosis of malignant hemangioendothelioma was made from these histological findings. Malignant hemangioendothelioma is rare, but is an important cause of intractable hemoptysis.     

Early deaths during tuberculosis treatment are associated with depressed innate responses, bacterial infection, and tuberculosis progression

Up to 14% of Malawian adults die during the intensive phase of tuberculosis treatment. In a prospective cohort of 199 Malawian adults with microbiologically confirmed pulmonary tuberculosis, clinical and laboratory parameters were compared between those who died or deteriorated with those who had an uneventful recovery. Baseline tumor necrosis factor alpha responses to stimulation with heat-killed Mycobacterium tuberculosis and lipopolysaccharide were reduced among the 22 patients with poor outcome (P = .017). Low body mass index (P = .002) and elevated respiratory rate (P = .01) at tuberculosis diagnosis independently predicted poor outcome. Validation of a clinical score identifying high-risk individuals is warranted, together with further investigation of immunological derangements.