摘要
尽管许多肿瘤的基因治疗策略旨在以消灭肿瘤细胞为最终目标，抑制肿瘤生长，并赋予较长生存时间，增强抗肿瘤免疫反应并诱导长期免疫监视同样重要。先天免疫应答不仅在适应性免疫应答的诱导中起着重要的作用，且具有抗癌活性。因此，通过激发先天免疫系统的新的治疗策略，在提高抗肿瘤活性方面或许具有一定的积极作用。
分子佐剂是一种可以协同刺激适应性和先天免疫反应的分子。此外，这些佐剂不仅可以激活NK细胞，而且可以刺激先天免疫系统产生细胞因子。因此，关于这些分子的研究主要集中在疫苗开发方面。虽然目前只有两种佐剂批准应用于临床，而其他分子佐剂，包括细胞因子，细菌产物，热休克蛋白，病毒样颗粒，免疫刺激复合物均已进行了广泛的研究。然而，许多分子佐剂因其副作用而不能应用于临床。本研究中，我们致力于使用一种完全无毒的佐剂，即NDVHN作为分子免疫佐剂。
在早期研究中，我们获得了一种基于肿瘤细胞选择性诱导凋亡基因的溶瘤腺病毒Ad-Apoptin。Ad-Apoptin可以产生较强的抗肿瘤和体外诱导细胞凋亡作用，而且对体内实体肿瘤具有显著的抗癌活性。此外，Ad-Apoptin具有抑制肿瘤转移的能力。近来发现，通过系统给药Ad-Apoptin可以直接抑制肿瘤生长。基于Ad-Apoptin的治疗特性，我们致力于评价使用重组腺病毒作为抗肿瘤基因治疗的候选策略。然而，重组体缺少免疫刺激能力，这使得它不能获得长时间的抗肿瘤活性。
新城疫病毒属于副粘病毒属，负股单链RNA病毒，通常导致大量家禽呼吸道和胃肠道的炎症。HN是一个74kDa的多功能膜II类糖蛋白，是NDV的主要结构蛋白之一。该蛋白不仅介导唾液酸包含受体的识别，而且具有NA，可以将唾液酸从这些受体上分离。研究表明，HN可以刺激外周血单个核细胞（PBMC）中干扰素-α应答。HN蛋白能促使T细胞产生共刺激功能并诱导先天免疫活性，且HN也具有I型干扰素的诱导能力。此外，NDV HN通过触发NKp44和NKp46的受体直接激活人体NK细胞。
抗肿瘤免疫可以是先天的或是适应的。虽然适应性抗肿瘤免疫活性可以诱导对特定抗原的反应，诱导产生持久免疫记忆，并对正常组织的毒性低，但先天免疫方法也可能是有益的。事实上，一般认为最有效的免疫抗瘤反应是先天的免疫方法。NK细胞是先天免疫系统的重要组成部分，其特点是快速应答并有极强的杀伤活性，而无需预先致敏及主要组织相容性分子的参与。NK不仅能够通过NK细胞表面表达的TNF相关的凋亡诱导配体（TRAIL）、Fas配体（FasL）或通过NK细胞分泌的TNF-α来实现细胞毒性作用，而且可能通过产生IFN-γ、白细胞介素和生长因子调节免疫应答。此外，在免疫应答过程中，NK细胞产生的许多趋化因子对树突状细胞（DC）、巨噬细胞和中性粒细胞产生影响。本研究采用NDV HN激活NK、DC和单核细胞，并稳定激活T细胞，这突显了HN基因佐剂在肿瘤治疗方面的潜在活性。
在这项研究中，我们采用HN作为肿瘤治疗的一个潜在的分子免疫佐剂。研究表明，Ad-HN能够在体外诱导外周血单个核细胞分泌淋巴因子效应细胞因子。此外，Ad-HN佐剂与对照佐剂相比，促使减少肿瘤的生长并提供生存益处。因此，HN在肿瘤基因治疗方面是一个合适的免疫佐剂。
本研究表明SGC7901细胞中成功表达的HN可执行NA和HA的功能。我们进一步确定含HN的SGC7901细胞可诱导PBMCs分泌淋巴因子效应细胞因子TNF-α，IFN-α和IFN-γ的增加。TNF-α可促进巨噬细胞的抗肿瘤细胞毒作用，NK细胞释放的IFN-γ能促进Th1细胞极化和随后的细胞毒T淋巴细胞的诱导。此外，IFN-α具有抗肿瘤作用以及对免疫细胞的多种活性。所有这些均有助于各种直接和间接的抗肿瘤效应的功能。接着，我们表明，NK细胞与Ad-HN感染的SGC7901细胞孵育后可增强NK细胞对未感染靶细胞的杀伤能力，这将有助于体内的溶瘤作用。
我们还设置了HN佐剂与Ad-Apoptin联合应用的治疗肿瘤模型，实验数据显示，用Ad-Apoptin治疗并随后用Ad-HN作为佐剂辅助治疗与单独Ad-Apoptin治疗的荷瘤小鼠相比肿瘤负荷减少。我们还观察到应用NDV HN作为免疫佐剂实验组具有明显的生存益处。这可能是由于凋亡素基因和HN之间的协同反应。因为凋亡素可以阻碍肿瘤的迅速增长，同时，HN建立了免疫防御防止肿瘤的渗透，扩散和转移。
总之，体外实验和缺乏适应性免疫系统体内肿瘤模型结果表明，先天免疫反应，尤其是NK细胞，通过佐剂HN在抑制同基因移植和改善平均生存期方面起着关键的作用。结果进一步加强了HN基因在肿瘤的治疗上潜在的佐剂活性。
Although many cancer gene therapy strategies aim at eradicating tumor cellswith the final goal to restrain tumor growth and confer longer survival time,augmentation of anti-tumor immune responses and induction of long-term immunesurveillance are coordinative important. Innate immunity not only plays an importantrole in the induction of adaptive immune responses but contributes to anticanceractivities. Therefore, novel therapeutic strategies including triggering of the innatearm of the immune system may be successful in increasing anti-tumor activity.
Molecular adjuvants are kinds of molecules that can synergic stimulate adaptiveand innate immune responses. Furthermore, these adjuvants can not only activate NKbut stimulate innate immune system to produce cytokines. Therefore the studies aboutthese molecules most focus on vaccine development. Although there are only twoadjuvants were currently permitted for clinical use, other molecular adjuvants,including cytokines, bacterial product, heat shock protein, virus like particles andimmunostimulatory complexes, are extensively researched. However, many of themolecules have side effects which make them fail in clinical using. In this study, tofulfill the highlighted demand for non-toxic adjuvants, we investigated the use ofNDV HN as a molecular immune adjuvant.
In our previous studies, we generated an oncolytic adenovirus Ad-Apoptin basedon a cancer cell selective apoptosis-inducing gene. It was shown that Ad-Apoptincould perform strong antitumor and apoptosis-inducing effects in vitro. It also couldconfer significant anticancer activity toward solid tumors in vivo. In addition,Ad-Apoptin was shown to be capable of suppressing metastatic nodules. Recently, Ad-Apoptin was shown to directly restrain tumor growth via system delivering.Because of these therapeutic properties of Ad-Apoptin, we sought to evaluate the useof the recombinant adenovirus as a candidate of anti-tumor gene therapy. However,the recombinant was absence of immune stimulating capacities, which made itinadequate to obtain prolonged anti-tumor activity.
NDV is a paramyxovirus with a negative single-stranded RNA genome whichcauses inflammation of the respiratory and gastrointestinal tract in a wide variety ofpoultry species. HN, a74kDa multifunctional membrane class II glycoprotein, is oneof the most important structural proteins of NDV. The protein can not only mediatesrecognition of sialic acid containing receptors but also possesses NA which cancleave the sialic acid on those receptors. It was demonstrated that HN could stimulatea strong interferon-α response in peripheral blood mononuclear cells (PBMCs). It wasshown that HN protein could confer T cell co-stimulatory function and inducinginnate immune activities. Furthermore, HN had also the type I interferons inducingcapacities. Additionally, NDV HN was shown to directly activate human NK cells viatriggering the NKp44and NKp46receptors.
Antitumor immunity can be either innate or adaptive. Although adaptiveantitumor immune activity can induce reactivity against defined antigens, induce longlasting immune memory, and give low toxicity to normal tissues, innate approachesmay also be of benefit. In fact, the most effective immunological antitumor responseshave been seen with active innate approaches. NK, a key component of the innateimmune system, is characterized by their rapid response and strong cytolytic activitywithout pre-sensitization and involving of major histocompatibility molecules. NKcan not only carry out cytotoxicity through the expression of TNF-related apoptosisinducing ligand (TRAIL) or Fas ligand (FasL) on the NK cell surface or TNF-αsecretion by NK cell, but regulate immune responses through produce IFN-γ,interleukins and growth factors. Furthermore, NK cells produce many chemokinesthat impact dendritic cells (DCs), macrophages and neutrophils during an immuneresponse. NDV HN used in present study can activate NK, DCs, monocytes, and stabilize activated T cells. This highlights the potential adjuvant activity of the HNgene in tumor therapy.
In this study, we approached the use of HN as a potential molecular immuneadjuvant in tumor therapy. We demonstrated that Ad-HN was capable of inducinglymphokine effector cytokines of PBMCs in vitro. In addition, Ad-HN adjuvant led toreduction of tumor growth and provided survival benefits when compared to thecontrol adjuvants. Therefore, it is plausible that HN is a suitable immune adjuvant forcancer gene therapy.
We demonstrated here that HN successfully expressed in SGC7901cellsperform both NA and HA. We further shown that SGC7901cells carrying HNinduced PBMCs to secrete increased amounts of lymphokine effector cytokinesTNF-α, IFN-α and IFN-γ. It was known that TNF-α could contribute to the antitumorcytotoxicity of activated macrophages, and IFN-γ released by NK could promote Th1cell polarization and subsequent cytotoxic-T-lymphocyte induction. Additionally,IFN-α could exhibit anti-tumor effects as well as had multiple activities on immunecells. All these might be contribute to variety of direct and indirect antitumor effectorfunctions. Subsequently, we showed that the incubation of NK cells withAd-HN-infected SGC7901cells was able to enhance the cytotoxic activity of NKagainst uninfected target cells, which might be contribute to the in vivo oncolyticproperties.
We also investigated in settings of therapeutic antitumor model whether HNadjuvant co-application with Ad-Apoptin could improve effectivity. Data showed areduction of tumor burden in tumor bearing mice upon therapeutic treatment withAd-Apoptin and subsequently Ad-HN as adjuvant in comparison to Ad-Apoptintreatment alone. We further observed remarkable survival benefits in the group ofapplication of NDV HN as an immune adjuvant. All these might be due to thesynergistic reaction between Apoptin and HN. Since Apoptin could obstruct theprompt growth of the tumors, meanwhile HN established the immunological defenseagainst the infiltration, the diffusion and the metastasis of the tumors.
In conclusion, the results from in vitro experiments and in vivo tumor modellack of adaptive immune system suggested that innate immune response, most likelyinvolving NK cells, plays a key role in the suppression of syngeneic graft andimprovement of the mean survival directed by adjuvant property of HN. The resultsfurther reinforced the potential adjuvant activity of the HN gene in tumor therapy.
引文
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