基于溶瘤腺病毒抗肿瘤免疫治疗的前景与展望

机体免疫系统在抗肿瘤过程中有着巨大的潜力,但肿瘤微环境(tumor microenvironment,TME)的免疫抑制状态可引发一系列的肿瘤免疫逃逸反应,这将使得癌症进一步恶化。溶瘤腺病毒(oncolytic adenovirus,OAds)可通过选择性复制及其溶瘤作用杀伤肿瘤细胞,暴露肿瘤相关抗原,活化免疫细胞,逆转TME,最终可引发一系列抗肿瘤免疫反应。OAds存在靶向性低、免疫原性强等缺陷,其免疫治疗效果不佳,若对其改造则能提高肿瘤靶向性,降低免疫原性,同时携带免疫治疗基因,显著提高抑癌活性。该文综述了肿瘤免疫治疗的相关机制及OAds抗肿瘤免疫治疗的研究进展。     

MicroRNA在肿瘤发生发展和诊断中作用的研究进展

microRNA是一类由内源基因编码的长度约为18-25个核苷酸的非编码单链RNA分子,可以与靶基因mRNA的3'非编码区结合,通过降解靶m RNA或(和)抑制靶m RNA转录后翻译调节靶蛋白的生成,从而发挥其生物学作用。目前,在人体基因组内发现的microRNA已经超过2500多个,可能调节着人类1/3的基因,在维持正常干细胞功能、调控细胞增殖分化及恶性肿瘤发生过程中均起重要作用。既往的研究表明microRNA与基因之间相互调控的失衡导致肿瘤的发生。从分子水平上研究microRNA与肿瘤发生的关系,检测microRNA与肿瘤相关基因表达情况的改变,分析肿瘤组织和血清中microRNA表达量与肿瘤分型的关系,将有利于肿瘤的病因学研究,早期发现和肿瘤治疗及预后判断。本文主要就microRNA在肿瘤发生发展和诊断中作用的研究进展进行了综述。     

免疫检查点阻断剂促进T细胞应答的影响因素

抑制免疫调节检查点,比如PD-1/PD-L1与CTLA-4,是癌症免疫治疗的前沿科学。然而这样的免疫疗法只对少部分患者的癌症形成有效。本文通过分析肿瘤的成瘤原因、微环境及其自体相关因素后发现这些因素均会导致免疫检查点阻断剂在体内失去T细胞免疫应答。因此,本文描述了免疫系统与宿主肠道微生物群可调控癌症免疫治疗的应答,并且在使用免疫检查点阻断剂的同时或之前调节肠道微生物群可以优化治疗效果。     

NF-κB家族成员RelA的翻译后修饰及其生理病理作用的研究进展

真核细胞转录因子NF-κB通过调节多种靶基因表达,参与炎症、免疫反应、程序性细胞死亡、细胞增殖和分化的调控。RelA是NF-κB家族一个重要的成员,其翻译后修饰可精准调控NF-κB的转录活性,在调节炎症、肿瘤、代谢以及免疫应答等重要的生命活动及相关疾病的发生发展过程中起重要作用。现总结相关领域最新研究进展,综述RelA翻译后修饰的种类、调控机制,对NF-κB通路功能的影响,及其在NF-κB介导的炎症、癌症等多种疾病中的功能。     

肝癌免疫治疗的研究进展

肝细胞肝癌是全球发病率和死亡率最高的恶性肿瘤之一,发病率和死亡率呈逐年上升趋势。我国是肝癌大国,每年肝癌的死亡病例数位居全球第一。免疫治疗是继手术、化疗和放疗之后新兴的癌症治疗手段,其通过解除肿瘤微环境对免疫细胞的抑制作用并激活机体免疫功能,实现控制和杀伤肿瘤细胞。常用的免疫治疗的方法有免疫检查点治疗、过继免疫治疗和肿瘤疫苗治疗等。与传统治疗手段相比,免疫治疗因具有增强机体免疫功能、延缓肿瘤进展、延长患者生存时间等优点,逐渐成为基础和临床研究的热点。文中就免疫治疗在肝癌领域的研究进展作一综述。     

调节性T细胞与胶质瘤的免疫治疗

调节性T细胞（regulatory T cell,Treg）是一群具有抑制其它免疫细胞功能的起负性调控的细胞群. Treg细胞能抑制多种免疫细胞,如CD4+T和CD8+T淋巴细胞、NK细胞、B淋巴细胞以及树突状细胞的活化和增殖,是体内维持免疫系统稳定,防止出现自身免疫性疾病重要因素.最新研究表明,Treg细胞在肿瘤免疫逃逸中也发挥重要作用. 肿瘤细胞通过扩增或招募Treg细胞,抑制机体对肿瘤的免疫作用,由此可知,Treg细胞在肿瘤的发生和发展过程中发挥重要作用. 因此,抑制Treg细胞的活性和数量是包括胶质瘤在内的肿瘤免疫治疗有效的方式.     

微RNA与免疫系统

微RNA(microRNA,miR)是一类进化上非常保守且不具蛋白质编码作用的小RNA分子,通过降解或阻遏信使RNA(mRNA)在转录后水平起到基因表达调控的作用。据估计人类基因组中含有约1000个miR,它们调控至少30%的人类蛋白质编码基因。miR参与体内多种生物学进程,包括细胞的增殖、分化、发育、凋亡、肿瘤发生和免疫反应。越来越多的证据表明miR在免疫细胞的分化和发育、天然免疫和适应性免疫反应的调节方面起到重要的作用。本文就miR及其在免疫系统的调节方面做一综述。     

白细胞介素33在肿瘤免疫中的作用及信号通路研究进展

白细胞介素33(interleukin-33,IL-33)主要表达于人角质细胞、内皮细胞和纤维母细胞中。IL-33在Th(helper T cell)2细胞的成熟中发挥重要作用,促进Th2细胞分泌Th2相关细胞因子,趋化Th2细胞,并在组织损伤中作为警报素放大免疫反应。IL-33也可以激活肥大细胞、嗜碱性粒细胞、嗜酸性粒细胞和自然杀伤细胞。随着肿瘤免疫疗法研究逐渐深入,IL-33的抗肿瘤作用也逐渐被人们认识,包括在黑色素瘤和乳腺癌等癌症中的作用。为更好总结IL-33在肿瘤免疫中的研究进展,本文从IL-33在肿瘤免疫中的信号通路和IL-33对不同肿瘤免疫治疗效应两方面进行了归纳和总结。     

固有免疫细胞及其模式识别受体与表观遗传学调控研究进展

固有免疫细胞是机体抵御病原微生物的首道防线,亦是机体有效启动和维持免疫反应的重要参与者,而模式识别受体是固有免疫细胞发挥免疫功能的重要免疫分子,因此,机体对固有免疫细胞及其模式识别受体的精细调控尤为重要。表观遗传学是近年研究热点,其在固有免疫调节中的作用逐渐受到重视。就近年表观遗传学中的DNA甲基化、组蛋白共价修饰及非编码RNA等在调节固有免疫细胞分化发育及其模式识别受体的相关研究作一简述,以期为感染、炎症、自身免疫病等研究与防治提供新的思路和策略。     

PD-L1基因表达的调控机制

程序性死亡配体-1(programmed death ligand-1, PD-L1)在人类多种恶性肿瘤细胞中高表达。肿瘤细胞上的PD-L1与T细胞上的PD-1结合从而抑制T细胞活性,导致肿瘤免疫逃逸。阻断PD-1/PD-L1相互作用的抗体有助于重新激活细胞毒性T细胞,从而消灭癌细胞。近年来,临床上针对PD-1/PD-L1免疫检查点的药物在人类癌症治疗中卓有成效。阐明PD-L1基因表达调控的分子机制可以加深对肿瘤免疫逃逸机理的认识,对临床肿瘤免疫治疗具有重要意义。本文主要从基因变异、表观遗传修饰、转录调控、microRNA与翻译后修饰等方面综述了PD-L1基因表达调控的研究进展。     

缺氧诱导因子与肾细胞癌关系的研究进展

缺氧诱导因子(hypoxia inducible factor,HIF)对维持肿瘤细胞的能量代谢、肿瘤血管生成、促进肿瘤细胞增殖和转移起着重要作用,是肿瘤细胞低氧条件下产生的关键信号分子。本综述旨在总结前人研究,阐述HIF与肾癌细胞之间的内在关系。HIF成员是参与肾癌细胞对缺氧应答反应中的关键因子,并通过靶基因的调节,促进新生血管的生成,导致肿瘤生长。其中,HIF-1α及HIF-2α在促进新生血管的生成方面发挥着主要作用。HIF-1α及HIF-2α与VEGF密切相关,随着其的表达增高,VEGF在数量上及m RNA水平上均显著增高,显示其可通过调控VEGF参与肾癌血管生成,而HIF-2α转录激活VEGF m RNA的特异性较HIF-1α更强。HIF-3α可能存在的负性调控作用,其异构体-4的作用可能与HIF-lα的负性调节有关,其可以阻止HIF-lα与下游靶基因的缺氧反应元件(hypoxia response elements,HRE)结合,同时可在转录水平抑制HIF-lα。HIF在未来可能有成为肾细胞癌治疗的靶点。     

Toll样受体与肿瘤免疫

Toll样受体(Toll-like receptor)是天然免疫系统中最重要的模式识别受体,在病原体感染过程中对入侵病原体的识别,激活免疫应答起重要作用。近年发现Toll样受体在多种肿瘤的发生过程中起重要的调控作用。Toll样受体在肿瘤细胞中具有表达,并且Toll样受体信号诱导的促炎症反应是肿瘤发生的必要条件,但是有些Toll样受体的配体仍然表现出极强的抗肿瘤活性,目前,Toll样受体在肿瘤免疫中的机制研究已经成为Toll样受体作为药物靶点的临床应用的关键。本文对Toll样受体在肿瘤免疫中的机制进行综述。     

Interleukin 18: Friend or foe in cancer

In the last few years, the field of tumor immunology has significantly expanded and its boundaries, never particularly clear, have become less distinct. Although the immune system plays an important role in controlling tumor growth, it has also become clear that tumor growth can be promoted by inflammatory immune responses. A good example that exemplifies the ambiguous role of the immune system in cancer progression is represented by interleukin 18 (IL-18) that was first identified as an interferon-γ-inducing factor (IGIF) involved in T helper type-1 (Th1) immune response. The expression and secretion of IL-18 have been observed in various cell types from immune cells to circulating cancer cells. In this review we highlighted the multiple roles played by IL-18 in immune regulation, cancer progression and angiogenesis and the clinical potential that may result from such understanding.     

Role of osteopontin in dendritic cell shaping of immune responses

Osteopontin (OPN) is a pleiotropic cytokine produced both by immune and non-immune cells and active on different cellular targets. OPN production has been associated with several pathological conditions, including autoimmune diseases (e.g. lupus, multiple sclerosis and rheumatoid arthritis) and cancer. Emerging evidence suggests that the role of OPN has been underestimated, as it seems to be working at multiple levels of immune regulation, such as the shaping of T cell effector responses, the regulation of the tumor microenvironment, and the functional interaction with mesenchymal stromal cells. In this context, dendritic cells (DCs) play a crucial role being both an important source and a cellular target for OPN action. DC family is composed by several cell subsets endowed with specific immune functions. OPN exerts its biological functions through multiple receptors and is produced in different intracellular and secreted forms. OPN production by DC subsets is emerging as a crucial mechanism of regulation in normal and pathological conditions and starts to be exploited as a therapeutic target. This review will focus on the role of DC-derived OPN in shaping immune response and on the complex role of this cytokines in the regulation in immune response.     

Network Modeling Identifies Molecular Functions Targeted by miR-204 to Suppress Head and Neck Tumor Metastasis

Due to the large number of putative microRNA gene targets predicted by sequence-alignment databases and the relative low accuracy of such predictions which are conducted independently of biological context by design, systematic experimental identification and validation of every functional microRNA target is currently challenging. Consequently, biological studies have yet to identify, on a genome scale, key regulatory networks perturbed by altered microRNA functions in the context of cancer. In this report, we demonstrate for the first time how phenotypic knowledge of inheritable cancer traits and of risk factor loci can be utilized jointly with gene expression analysis to efficiently prioritize deregulated microRNAs for biological characterization. Using this approach we characterize miR-204 as a tumor suppressor microRNA and uncover previously unknown connections between microRNA regulation, network topology, and expression dynamics. Specifically, we validate 18 gene targets of miR-204 that show elevated mRNA expression and are enriched in biological processes associated with tumor progression in squamous cell carcinoma of the head and neck (HNSCC). We further demonstrate the enrichment of bottleneckness, a key molecular network topology, among miR-204 gene targets. Restoration of miR-204 function in HNSCC cell lines inhibits the expression of its functionally related gene targets, leads to the reduced adhesion, migration and invasion in vitro and attenuates experimental lung metastasis in vivo. As importantly, our investigation also provides experimental evidence linking the function of microRNAs that are located in the cancer-associated genomic regions (CAGRs) to the observed predisposition to human cancers. Specifically, we show miR-204 may serve as a tumor suppressor gene at the 9q21.1–22.3 CAGR locus, a well established risk factor locus in head and neck cancers for which tumor suppressor genes have not been identified. This new strategy that integrates expression profiling, genetics and novel computational biology approaches provides for improved efficiency in characterization and modeling of microRNA functions in cancer as compared to the state of art and is applicable to the investigation of microRNA functions in other biological processes and diseases.     

TGFbeta in Cancer

The transforming growth factor beta (TGFbeta) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development. The regulatory cytokine TGFbeta exerts tumor-suppressive effects that cancer cells must elude for malignant evolution. Yet, paradoxically, TGFbeta also modulates processes such as cell invasion, immune regulation, and microenvironment modification that cancer cells may exploit to their advantage. Consequently, the output of a TGFbeta response is highly contextual throughout development, across different tissues, and also in cancer. The mechanistic basis and clinical relevance of TGFbeta's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway.