Mechanism of Eliciting Antitumor Cell Immunity Via Lentivector Immunization

通过慢载体免疫引发抗肿瘤细胞免疫的机制

基本信息

批准号：
8018491
负责人：
YUKAI HE
金额：
$ 27.09万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8018491
关键词：
Antigen Presentation Antigen-Presenting Cells Antigens Blood CD8B1 gene Cell physiology Cells Clinical Cross Presentation Cross-Priming Cutaneous Administration Data Degradation Pathway Dendritic Cells Dermal Development Dopachrome isomerase Effectiveness Effector Cell Engineering Epitopes Fc Immunoglobulins Fc Receptor Future Generations Goals Immune Immune response Immune system Immunity Immunization Immunotherapy In Vitro Infectious Skin Diseases Interphase Cell Invaded Knowledge Langerhans cell Malignant Neoplasms Mediating Microbe Modality Modeling Mus Pathway interactions Pattern recognition receptor Population Preventive Process Role Simplexvirus Skin Stimulus T cell response T-Lymphocyte Testing Therapeutic Toll-like receptors Tumor Antigens Ubiquitin Vaccines Vaccinia virus Virus Diseases antigen processing autocrine base cancer immunotherapy design genetic immunization strategies improved in vivo influenzavirus melanoma multicatalytic endopeptidase complex paracrine protein degradation response tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Immunotherapy represents one of the most promising therapeutic modalities for cancer. However, the immune responses induced by current immunization approaches are generally insufficient to generate adequate clinical responses. Development of effective immunization approaches ultimately require rational designs based on detailed knowledge of how immune cells are activated. The antigen presenting function of DCs as whole population is well established, but the role of each distinct DC subset has not been defined but is critical for developing targeted effective immunization approaches. In this proposal we will focus our effort on understanding the roles of the different DC subsets in lentivector mediated genetic immunization and the mechanism of how T cell immune response is elicited. We hypothesize that cutaneous administration of lentivector will result in specific transduction of skin DCs (sDCs) and direct priming of naive T cells, which can exploited for designing more effective antitumor genetic immunization strategies. The specific Aims are as follows: Aim 1: To investigate the mechanism of T cell priming in lentivector immunization; Aim 2: To manipulate antigen processing pathways to elicit more effective T cell responses; and Aim 3: To evaluate the antitumor effectiveness of lentivector immunization. To accomplish these aims, DC subsets from lentivector immunized mice will be examined for their function of priming naive T cells ex vivo and in vivo. The mechanism of direct vs cross priming of naive T cells will be determined in vivo. In addition, the potential of utilizing lentivector immunization in inducing T cell immune responses against self tumor antigen will also be investigated. Promotion of endogenous antigen processing by ubiquitin mediated degradation pathway and exogenous antigen presentation by Fc receptor will be investigated to enhance T cell responses against melanoma self tumor Ag TRP-2. Our study will yield information pertinent to DC subsets that activate T cells in vivo, the mechanism how T cell are primed in vivo, and the potential of lentivector immunization in eliciting T cell responses against self tumor Ag. The knowledge gained from these studies will assist the design of more effective and safer genetic immunization approaches for antitumor immunotherapy.

描述（由申请人提供）：免疫疗法代表了最有前途的癌症治疗方式之一。然而，当前免疫方法诱导的免疫反应通常不足以产生足够的临床反应。有效免疫方法的开发最终需要基于免疫细胞如何激活的详细知识的合理设计。 DC 作为整个群体的抗原呈递功能已得到充分确立，但每个不同 DC 亚群的作用尚未确定，但对于开发有针对性的有效免疫方法至关重要。在本提案中，我们将集中精力了解不同 DC 亚群在慢载体介导的基因免疫中的作用以及如何引发 T 细胞免疫反应的机制。我们假设慢载体的皮肤给药将导致皮肤 DC (sDC) 的特异性转导和初始 T 细胞的直接启动，这可用于设计更有效的抗肿瘤遗传免疫策略。具体目的如下：目的1：研究慢载体免疫中T细胞启动的机制；目标 2：操纵抗原加工途径以引发更有效的 T 细胞反应；目标3：评估慢载体免疫的抗肿瘤效果。为了实现这些目标，将检查慢载体免疫小鼠的 DC 亚群在离体和体内启动幼稚 T 细胞的功能。初始 T 细胞的直接与交叉引发机制将在体内确定。此外，还将研究利用慢载体免疫诱导针对自身肿瘤抗原的 T 细胞免疫应答的潜力。将研究泛素介导的降解途径促进内源抗原加工和 Fc 受体呈递外源抗原，以增强 T 细胞针对黑色素瘤自身肿瘤 Ag TRP-2 的反应。我们的研究将产生与体内激活 T 细胞的 DC 亚群相关的信息、T 细胞在体内启动的机制，以及慢病毒载体免疫在引发针对自身肿瘤 Ag 的 T 细胞反应中的潜力。从这些研究中获得的知识将有助于设计更有效、更安全的抗肿瘤免疫治疗基因免疫方法。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Local administration of TLR ligands rescues the function of tumor-infiltrating CD8 T cells and enhances the antitumor effect of lentivector immunization.

TLR配体的局部给药可挽救肿瘤浸润CD8 T细胞的功能并增强慢载体免疫的抗肿瘤效果。

DOI：
发表时间：
2013-06-01
期刊：
影响因子：
0
作者：
Xiao, Haiyan;Peng, Yibing;Hong, Yuan;Huang, Lei;Guo, Z Sheng;Bartlett, David L;Fu, Ning;Munn, David H;Mellor, Andrew;He, Yukai
通讯作者：
He, Yukai

Immunoglobulin Fc fragment tagging allows strong activation of endogenous CD4 T cells to reshape the tumor milieu and enhance the antitumor effect of lentivector immunization.

免疫球蛋白Fc片段标记可以强烈激活内源性CD4 T细胞，重塑肿瘤环境并增强慢载体免疫的抗肿瘤效果。

DOI：
发表时间：
2012-05-15
期刊：
影响因子：
0
作者：
Hong Y;Peng Y;Xiao H;Mi M;Munn D;He Y
通讯作者：
He Y

Lentivector expressing HBsAg and immunoglobulin Fc fusion antigen induces potent immune responses and results in seroconversion in HBsAg transgenic mice.

表达 HBsAg 和免疫球蛋白 Fc 融合抗原的慢病毒载体可诱导有效的免疫反应，并导致 HBsAg 转基因小鼠的血清转化。

DOI：
发表时间：
2011-05-17
期刊：
影响因子：
5.5
作者：
Hong, Yuan;Peng, Yibing;Mi, Michael;Xiao, Haiyan;Munn, David H.;Wang, Gui-qiang;He, Yukai
通讯作者：
He, Yukai

Blockade of programmed death-1 pathway rescues the effector function of tumor-infiltrating T cells and enhances the antitumor efficacy of lentivector immunization.

阻断程序性死亡-1途径可挽救肿瘤浸润T细胞的效应功能，并增强慢载体免疫的抗肿瘤功效。

DOI：
发表时间：
2010-11-01
期刊：
影响因子：
0
作者：
Zhou, Qifeng;Xiao, Haiyan;Liu, Yanjun;Peng, Yibing;Hong, Yuan;Yagita, Hideo;Chandler, Phillip;Munn, David H;Mellor, Andrew;Fu, Ning;He, Yukai
通讯作者：
He, Yukai

Lentivector immunization stimulates potent CD8 T cell responses against melanoma self-antigen tyrosinase-related protein 1 and generates antitumor immunity in mice.

慢病毒载体免疫可刺激 CD8 T 细胞针对黑色素瘤自身抗原酪氨酸酶相关蛋白 1 的有效反应，并在小鼠中产生抗肿瘤免疫力。