溶瘤呼肠孤病毒在肿瘤生物治疗中作用的研究进展

肿瘤生物治疗的重要性日渐获得各方关注，而溶瘤病毒疗法作为肿瘤免疫治疗的一个分支也已成为研究热点。呼肠孤病毒（ReoV）地缘分布广泛，因其天然对肿瘤细胞具有靶向性及人体感染后几乎无症状而被认为是理想的溶瘤病毒载体，目前被广泛应用于临床试验。肿瘤细胞常伴有RAS基因的过度表达，会抑制对病毒有拮抗作用的激酶表达，造成ReoV大量复制致使肿瘤细胞发生凋亡、坏死、自噬等直接溶瘤效应；此外，ReoV 感染肿瘤细胞后释放的促炎性细胞因子和趋化因子逆转了TME的免疫抑制状态，可激活并招募固有免疫效应细胞杀死肿瘤细胞，并促进适应性抗肿瘤免疫反应的产生。另外，ReoV与放化疗、其他免疫制剂的联用可增强了肿瘤治疗的效果。本文从溶瘤ReoV的生物学特性方面，重点介绍了ReoV的基本特征与感染机制及ReoV 的肿瘤嗜性；同时，总结了溶瘤ReoV 的溶瘤机制，主要包括ReoV 诱导程序性细胞死亡及ReoV 诱导非程序性死亡；概括了溶瘤ReoV 所诱导的抗肿瘤免疫反应，如溶瘤ReoV 诱导的抗肿瘤固有免疫、溶瘤ReoV 诱导的获得性抗肿瘤免疫等，并介绍了溶瘤ReoV联合用药的效果。随着溶瘤作用机制的探明及临床试验的开展，溶瘤ReoV在肿瘤的生物治疗中的应用将更为广阔。     

肿瘤微环境与炎症反应及溶瘤病毒治疗的关系

炎症反应在清除病原体、创伤愈合和抗肿瘤免疫中发挥重要作用,被肿瘤细胞劫持的炎性细胞和细胞因子也是肿瘤微环境重要的参与者;许多肿瘤起源于感染和慢性炎症,肿瘤微环境中炎症细胞和炎症介质的蓄积具有促进恶性细胞增殖和存活、促进血管生成和肿瘤转移,以及逆转获得性免疫反应的作用,也改变了肿瘤细胞对激素和化疗药物的敏感性。炎症反应在肿瘤的发生和消除中发挥的作用比较复杂。溶瘤病毒治疗肿瘤,是充分利用溶瘤病毒选择性感染和杀伤肿瘤细胞的特性。在肿瘤微环境中,溶瘤病毒所诱导的针对肿瘤细胞和病毒的天然免疫反应具有双重效应:既能引起肿瘤细胞的损伤,促进溶瘤病毒抗肿瘤的疗效,也能识别、清除隐藏于肿瘤组织内部的溶瘤病毒,降低溶瘤病毒的效应。     

细胞荷载溶瘤病毒治疗肿瘤的研究进展

静脉注射的溶瘤病毒可被免疫系统完全排除而不能发挥其抗肿瘤作用。研究表明,溶瘤病毒用细胞包装后可以有效避免病毒被机体免疫系统清除,同时,病毒和载体细胞的生物学活性不受影响;另外采用具有肿瘤细胞、肿瘤基质或肿瘤解剖定位靶向性的细胞载体,可以将病毒准确地输送至肿瘤病灶,有效发挥溶瘤病毒的抗肿瘤效应。本文将对细胞荷载溶瘤病毒治疗肿瘤方面的研究进展做一综述。     

放疗免疫调节效应研究的进展——从基础到临床

既往观点认为，放射治疗主要通过破坏肿瘤细胞脱氧核糖核酸双链直接发挥杀伤肿瘤细胞的作用，近年来研究发现，放疗也可通过上调局部与全身免疫反应，间接产生积极有效的抗肿瘤免疫应答。然而，放疗的免疫调节效应具有双面性，一方面可激活并产生抗肿瘤免疫促进效应，另一方面也可能产生免疫抑制作用。其中，放疗正向调节适应性与固有性抗肿瘤免疫反应的关键分子机制主要包括：诱导免疫原性细胞凋亡从而促进T淋巴细胞的增殖与活化；激活环磷酸鸟苷-腺苷合成酶-干扰素基因刺激蛋白通路引发Ⅰ型干扰素反应；改变肿瘤细胞表型，加强其免疫原性与抗原可视度；刺激肿瘤细胞与基质细胞释放多种炎症因子，重塑肿瘤免疫微环境；上调肿瘤细胞表面免疫检查点以及死亡受体等的表达，促进免疫识别与抗肿瘤免疫应答。而放疗负向抑制免疫反应的主要机制包括：诱导肿瘤细胞上调多种免疫抑制因子的基因表达；增强包括调节性T细胞、髓系来源抑制性细胞在内的多种免疫抑制细胞的功能与作用；导致淋巴细胞的数量减少以及免疫效应细胞的耗竭等。基于以上关于放疗免疫调节效应的机制原理探索，目前在放疗联合免疫治疗的临床实践中也显示出重大的研究进展，包括免疫治疗时代背景下的放疗远隔效应，...     

放疗对机体抗肿瘤免疫效应机制的影响

放疗主要通过对放射野内肿瘤细胞的杀伤使靶区内肿瘤得到控制、可以作用于远处转移灶并能够激活机体抗肿瘤免疫应答。越来越多的研究表明合理的放疗剂量和分割模式能够改善肿瘤微环境,诱导特异性 T 细胞免疫应答,形成原位疫苗并激活机体的抗肿瘤免疫效应。本文重点阐述放疗对机体抗肿瘤免疫效应机制的影响,以及放疗在免疫治疗的辅助下如何发挥抗肿瘤的作用,为恶性肿瘤治疗提供新思路。     

间充质干细胞作为溶瘤病毒细胞载体的研究进展

溶瘤病毒能够在肿瘤细胞内大量增殖并最终裂解肿瘤细胞,同时还具有对肿瘤微环境的调控作用,激发宿主抗肿瘤免疫反应。但是溶瘤病毒经静脉注射后引发的机体抗病毒免疫应答以及溶瘤病毒的肿瘤靶向性差,使得临床上对肿瘤的疗效不佳。间充质干细胞具有肿瘤趋向性、免疫抑制功能和旁分泌效应。间充质干细胞运载溶瘤病毒既可以保护病毒不被免疫系统清除又可精准将病毒递送到肿瘤病变部位,同时病毒感染可改变间充质干细胞分泌的细胞因子谱,促进机体抗肿瘤免疫反应。因此,间充质干细胞运载溶瘤病毒是治疗复发/难治性实体肿瘤的理想选择。本文结合临床前及临床研究的有关进展,对间充质干细胞运载溶瘤病毒治疗实体肿瘤进行综述,为间充质干细胞运载溶瘤病毒的临床应用提供了理论依据。     

溶瘤病毒疗法的研究现状与展望

针对癌症的传统治疗手段主要有手术治疗、化疗、放疗等。这些方法虽然能在一定程度上控制肿瘤生长,但也存在一定的技术局限性。溶瘤病毒疗法作为一种新型的肿瘤细胞生物疗法,为恶性肿瘤的治疗带来了新的发展希望。溶瘤病毒能够在不影响正常细胞的情况下,发挥较强的肿瘤抑制和杀伤作用,同时通过免疫诱导促使机体产生抗肿瘤免疫反应,进一步提高对肿瘤细胞的杀伤效果。然而,由于病毒自身存在较强的免疫原性,静脉注射后会引发机体产生不同程度的免疫应答,并且溶瘤病毒的肿瘤靶向性和单独治疗能力有限,使得其最终的肿瘤治疗效果并不理想。研究者通过设计并构建不同类型的载体来装载病毒,以封闭其固有的免疫原性,延长其血液循环时间的同时,进一步提高其对恶性肿瘤的靶向性,并在此基础上将溶瘤病毒与其他肿瘤治疗手段结合,进而增强溶瘤病毒的肿瘤治疗效果。本文将重点围绕如何有效构建溶瘤病毒载体及联合其他肿瘤治疗手段以提高溶瘤病毒的肿瘤治疗效果,对近期相关研究进展进行综述介绍。     

他汀类药物抗肿瘤作用机制

他汀类药物除有降胆固醇作用外,还对恶性肿瘤有一定的治疗作用.其可能的抗肿瘤作用机制为:诱导细胞凋亡及分化、抑制肿瘤细胞增殖、降低肿瘤细胞侵袭转移能力、联合增敏以及化学预防作用.     

CD44与肿瘤的免疫逃逸

CD44在多种肿瘤细胞表达上调或发生构型改变，通过多种机制参与远处侵袭转移。最新研究表明，CD44在肿瘤免疫逃逸中发挥重要作用，通过诱导肿瘤细胞Fas表达异常、抵抗凋亡及构型改变等多种机制参与肿瘤的免疫逃逸。     

携带溶瘤病毒细胞载体的研究进展

溶瘤病毒是一类具有复制能力的肿瘤杀伤性病毒,可通过多种机制发挥抗肿瘤作用。然而,机体的免疫监视作用使溶瘤病毒不能高效到达肿瘤部位而不足以治疗肿瘤。细胞载体作为溶瘤病毒的"特洛伊木马"可使溶瘤病毒逃避免疫监视,且两者联合具有更好的抗肿瘤疗效。根据细胞载体对肿瘤靶向程度的差异,细胞载体可分三大类:靶向肿瘤细胞的细胞载体,包括抗原特异性T细胞和细胞因子诱导的杀伤细胞;靶向肿瘤基质的细胞载体,包括间充质干细胞、内皮系细胞和肿瘤相关巨噬细胞;靶向组织或器官的细胞载体,包括外周血淋巴细胞、树突状细胞和肿瘤细胞等。本文主要介绍该三类细胞载体的研究及应用进展,讨论其存在的问题与应对对策,并展望未来发展方向。     

藤黄酸的抗肿瘤机制

目前发现藤黄酸可通过不同机制在多种肿瘤细胞中发挥抗肿瘤作用,包括诱导细胞凋亡,抑制端粒末端转移酶和拓扑异构酶活性,抑制热休克蛋白和通道蛋白表达,抑制肿瘤血管生成和转移,逆转肿瘤多药耐药,提示藤黄酸有望成为新型抗肿瘤药物,且仍需进一步探索其在抗肿瘤领域的价值.     

Modulation of viability and maturation of human monocyte-derived dendritic cells by oncolytic adenoviruses

Adenoviral oncolysis is a promising new modality for treatment of cancer based on selective viral replication in tumor cells. However, tumor cell killing by adenoviral oncolysis needs to be improved to achieve therapeutic benefit in the clinic. Towards this end, the activation of anti-tumor immunity by adenoviral oncolysis might constitute a potent mechanism for systemic killing of uninfected tumor cells, thereby effectively complementing direct tumor cell killing by the virus. Knowledge of anti-tumor immune induction by adenoviral oncolysis, however, is lacking mostly due to species-specificity of adenovirus replication, which has hampered studies of human oncolytic adenoviruses in animals. We suggest the analysis of interactions of oncolytic adenoviruses with human immune cells as rational basis for the implementation of adenoviral oncolysis-induced anti-tumor immune activation. The goal of our study was to investigate how oncolytic adenoviruses affect human dendritic cells (DCs), key regulators of innate and adoptive immunity that are widely investigated as tumor vaccines. We report that melanoma-directed oncolytic adenoviruses, like replication-deficient adenoviruses but unlike adenoviruses with unrestricted replication potential, are not toxic to monocyte-derived immature DCs and do not block DC maturation by external stimuli. Of note, this is in contrast to reports for other viruses/viral vectors and represents a prerequisite for anti-tumor immune activation by adenoviral oncolysis. Furthermore, we show that these oncolytic adenoviruses alone do not or only partially induce DC maturation. Thus additional signals are required for optimal immune activation. These could be delivered, for example, by inserting immunoregulatory transgenes into the oncolytic adenovirus genome.     

Targeted Hsp70 expression combined with CIK-activated immune reconstruction synergistically exerts antitumor efficacy in patient-derived hepatocellular carcinoma xenograft mouse models

The patient-derived tumor xenograft (PDTX) models can reproduce a similar natural genetic background and similar biological behaviors to tumor cells in patients, which is conducive to the assessment of personalized cancer treatment. In this study, to verify the targeting and effectiveness of the therapeutic strategy using a Survivin promoter-regulated oncolytic adenovirus expressing Hsp70, the PDTX models of hepatocellular carcinoma (HCC) were established in nude mice and the cytokine-induced killer (CIK) cells were intravenously infused into mice to partially reconstruct the mouse immune function. The results demonstrated that, either the immune anti-tumor effect caused by CIK cell infusion or the oncolytic effect generated by oncolytic adenovirus replication was very limited. However, the synergistic tumor inhibitory effect was significantly enhanced after treatments with oncolytic adenovirus expressing Hsp70 combined with CIK cells. Oncolytic adenovirus mediated the specific expression of Hsp70 in cancer tissues allowed the CIK chemotaxis, and induce the infiltration of CD3+ T cells in tumor stroma, thereby exhibiting anti-tumor activity. The anti-tumor effect was more effective for the highly malignant tumor xenografts with highly Survivin expression. This strategy can synergistically activate multiple anti-tumor mechanisms and exert effective anti-tumor activities that have a significant inhibitory effect against the growth of HCC xenografts.     

Host mediated anti-tumor effect of oncolytic Newcastle disease virus after locoregional application

Several strains of the Newcastle disease virus (NDV) have raised considerable interest in recent years for clinical application because of their oncolytic properties. In this study we characterized virological, immunological and anti-tumor properties of some NDV strains. The oncolytic strain MTH-68/H was the most potent interferon-alpha inducer and, after UV light inactivation, it was the only tested NDV strain which induced in human PBMC anti-tumor activity in vitro. Upon systemic application to mice bearing a virus susceptible intradermal tumor, no significant anti-tumor effects were observed with the two oncolytic strains Italian and MTH-68/H while the treatment had significant side effects as seen by loss of body weight. In contrast, when using a locoregional application model for treatment of liver metastases of luciferase transfected CT26 colon carcinoma cells, MTH-68/H showed a significant delay in tumor growth, as well as prolonged survival but no effects on body weight. Surprisingly, this CT26 murine tumor cell transfectant was resistant in vitro to virus infection and oncolysis. These results suggest: i) that locoregional application of oncolytic NDV is more effective than systemic i.v. application; and ii) that oncolytic NDV can mediate effects even against a virus-resistant tumor line. The involvement of host anti-tumor immune responses as an important mechanism in therapies based on oncolytic NDV will be discussed.     

外泌体在肿瘤发展中的研究进展

外泌体是细胞经过"内吞-融合-外排"等一系列调控过程而形成的细胞外纳米级小囊泡。外泌体可以携带蛋白,运送RNA,在细胞间物质和信息转导中起重要作用。外泌体可能通过调控免疫功能,促进肿瘤血管新生和肿瘤转移,以及直接作用于肿瘤细胞等途径,影响肿瘤的进展。外泌体可应用于肿瘤的诊断。本文总结了近年来有关外泌体在肿瘤发展中作用的研究进展。     

Berberine induces cell death in human hepatoma cells in vitro by downregulating CD147

The isoquinoline plant alkaloid berberine has anti-tumor effects on a variety of carcinoma cells, mainly through inhibition of cell proliferation, apoptosis induction and cell cycle arrest. However, the mechanisms underlying its role in tumor progression are unknown. In the present study, we investigated the molecular mechanisms involved in berberine-induced cell death in human hepatoma carcinoma cell (HCC) lines HepG2 and SMMC7721. Our results showed that berberine inhibited tumor cell viability in a dose- and time-dependent manner, and induced cell death via apoptosis and autophagy. Moreover, berberine treatment significantly inhibited CD147 expression by HCC cells in a dose-dependent manner. Overexpression of CD147 protein markedly reduced berberine-induced cell death. Our data provide the first experimental evidence that berberine induces cell death in HCC cells via downregulation of CD147 and suggest a new mechanism to explain its anti-tumor effects.     

热疗联合免疫检查点抑制剂的基础研究和临床应用进展北大核心CSCD

恶性肿瘤传统治疗方法对晚期转移患者疗效欠佳。近年来免疫检查点抑制剂治疗发展迅速,极具潜力,但整体临床有效率不高。肿瘤通过多种机制改变肿瘤微环境,产生免疫耐药,从而大大降低了免疫检查点抑制剂的疗效。热疗不仅可发挥热效应的抗肿瘤优势,还可通过多种途径起到直接和间接免疫增敏作用,将"冷肿瘤"转变为"热肿瘤",从而多方面起到增强免疫检查点抑制剂疗效的作用。大量基础实验证明,在小鼠体内进行热疗联合免疫检查点抑制剂已取得较好效果。目前,部分正在开展的热疗联合免疫检查点抑制剂临床试验也已取得较好进展。本文从免疫检查点抑制剂、热疗、热疗联合免疫检查点抑制剂3个层面分析了联用优势,并展望了未来热疗联合免疫检查点抑制剂治疗的重点研究方向。     

华蟾素抗肿瘤机制研究进展北大核心

华蟾素是根据传统中药蟾酥开发而成的现代中药,其主要成分为蟾毒内酯类、生物碱类、多肽类、胆固醇类等。随着对华蟾素药理作用的深入研究,华蟾素主要通过抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡、抑制肿瘤细胞远处转移、调节免疫反应等多种途径发挥抗肿瘤作用。本文通过对文献进行整理归纳发现,虽然华蟾素在抗肿瘤治疗中作用显著,仍需在以下几个方面有所突破:华蟾素主要作用机制尚需深入研究,包括其发挥抗肿瘤机制的作用靶点、有效单体、信号转导通路等;临床研究缺乏大样本、多中心、高质量的随机对照试验的临床研究;对于应用于肿瘤后的生存率方面的研究不足,缺乏远期疗效的评价,应加强长期随访观察。