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Activating robust immunity to tumor-associated antigens:mechanisms and biology

激活对肿瘤相关抗原的强大免疫力：机制和生物学

基本信息

批准号：
8447368
负责人：
Edith M Janssen
金额：
$ 28.38万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8447368
关键词：
Adjuvant Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Antigens Apoptotic Autoimmunity Autologous Tumor Cell Biology CD8B1 gene Cancer Vaccines Cell Count Cell Death Cells Chemicals Clinical Cross Presentation Cross-Priming DNA Data Dendritic Cells Development Equilibrium Feedback Goals Homeostasis IFNAR1 gene Immune Immune response Immune system Immunity Immunization Immunosuppressive Agents In Vitro Individual Inflammatory Interferons Kinetics Ligands Malignant Neoplasms Memory Modeling Molecular Mus Normal tissue morphology Nucleotides Predisposition Prevention Preventive Process Production RNA RNA Interference Recurrence Role Signal Pathway Structure T cell anergy T cell response T-Cell Activation T-Lymphocyte Therapeutic Tissues Tumor Antigens Vaccination Work autocrine base cell type cytokine design insight lymph nodes metastasis prevention neoplastic cell novel prevent public health relevance receptor response restoration sensor tumor uptake vaccination strategy

项目摘要

DESCRIPTION (provided by applicant): Therapeutic cancer vaccines are intended to drive specific activation of the immune system for therapy of existing malignancies or prevention of their recurrence. This requires powerful vaccination strategies, due to the preexisting immunosuppressive mechanisms orchestrated by the tumor. Theoretically, vaccination with apoptotic autologous tumor cells represents a particularly promising way to target the greatest number of potential antigens without the need for their individual identification. However, the sensing and clearance of apoptotic cells is generally considered to be a non-inflammatory or even tolerizing process. The prevailing view has been that apoptotic cells generated by normal tissue turnover are captured by dendritic cells (DCs) that migrate to local lymph nodes, where they induce T cell tolerance, T cell anergy, or T cell deletion in order to maintain tissue homeostasis and prevent autoimmunity in the host. We recently identified a novel DC subset (nDC), that, in contrast with other cross-presenting and cross-tolerizing DC subsets, potently (cross-)primes both CD4+ and CD8+T cells to cell-associated antigens after uptake of apoptotic material. The potent adjuvant activity of the nDC is largely dependent on their production of type I IFN after interacting with apoptotic cells. T cells primed by nDC display a greater capacity for primary expansion, cytokine production, and memory formation on a per cell basis than those primed by other DC subsets. As a consequence, these nDC are extremely potent in the induction of protective anti- tumor responses in both vaccination and therapeutic settings when exposed to apoptotic tumor cells. The central hypothesis underlying our proposed studies is that type I IFN production by nDC exposed to apoptotic cells is critical for nDC function and their subsequent priming of protective T cell responses to cell-associated antigens. The long-term goals of this work are two-fold: (1) definition of the molecular and cellular mechanisms in DCs that balance the pro- and anti-inflammatory immune response to self after cell death; and (2) translational exploitation of these mechanistic insights in order to devise effective therapeutic and preventive cancer vaccines.

描述（由申请人提供）：治疗性癌症疫苗旨在驱动免疫系统的特异性激活，以治疗现有的恶性肿瘤或预防其复发。由于肿瘤预先存在的免疫抑制机制，这需要强有力的疫苗接种策略。从理论上讲，用凋亡的自体肿瘤细胞接种疫苗是一种特别有前途的方法，可以靶向最多数量的潜在抗原，而无需对其进行单独鉴定。然而，凋亡细胞的感知和清除通常被认为是一个非炎症甚至耐受的过程。主流观点认为，由正常组织转换产生的凋亡细胞被迁移到局部淋巴结的树突状细胞（dc）捕获，在那里它们诱导T细胞耐受、T细胞能量或T细胞缺失，以维持组织稳态并防止宿主的自身免疫。我们最近发现了一种新的DC亚群（nDC），与其他交叉呈递和交叉耐受的DC亚群不同，它在摄取凋亡物质后有效地（交叉）将CD4+和CD8+T细胞引到细胞相关抗原上。nDC的有效佐剂活性很大程度上依赖于它们与凋亡细胞相互作用后产生I型IFN。与其他DC亚群启动的T细胞相比，nDC启动的T细胞显示出更大的原代扩增、细胞因子产生和记忆形成的能力。因此，当暴露于凋亡的肿瘤细胞时，这些nDC在疫苗接种和治疗环境中都能极有效地诱导保护性抗肿瘤反应。我们提出的研究的中心假设是，暴露于凋亡细胞的nDC产生I型IFN对于nDC功能及其随后启动对细胞相关抗原的保护性T细胞反应至关重要。这项工作的长期目标有两个方面：(1)定义dc在细胞死亡后平衡促炎性和抗炎性免疫反应的分子和细胞机制；(2)转化利用这些机制的见解，以设计有效的治疗和预防癌症疫苗。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prolonged antigen storage endows merocytic dendritic cells with enhanced capacity to prime anti-tumor responses in tumor-bearing mice.

DOI：
10.4049/jimmunol.1001619
发表时间：
2010-09-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Reboulet RA;Hennies CM;Garcia Z;Nierkens S;Janssen EM
通讯作者：
Janssen EM

Melanoma-infiltrating dendritic cells: Limitations and opportunities of mouse models.

DOI：
10.4161/onci.22660
发表时间：
2012-12-01
期刊：
Oncoimmunology
影响因子：
7.2
作者：
Klarquist JS;Janssen EM
通讯作者：
Janssen EM

Antigen cross-presentation by dendritic cell subsets: one general or all sergeants?

DOI：
10.1016/j.it.2013.02.007
发表时间：
2013-08
期刊：
Trends in immunology
影响因子：
16.8
作者：
Nierkens S;Tel J;Janssen E;Adema GJ
通讯作者：
Adema GJ

Cutting edge: merocytic dendritic cells break T cell tolerance to beta cell antigens in nonobese diabetic mouse diabetes.

DOI：
10.4049/jimmunol.1001398
发表时间：
2010-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Katz JD;Ondr JK;Opoka RJ;Garcia Z;Janssen EM
通讯作者：
Janssen EM

Plasmacytoid dendritic cells protect against atherosclerosis by tuning T-cell proliferation and activity.

DOI：
10.1161/circresaha.111.256529
发表时间：
2011-12-09
期刊：
Circulation research
影响因子：
20.1
作者：
Daissormont IT;Christ A;Temmerman L;Sampedro Millares S;Seijkens T;Manca M;Rousch M;Poggi M;Boon L;van der Loos C;Daemen M;Lutgens E;Halvorsen B;Aukrust P;Janssen E;Biessen EA
通讯作者：
Biessen EA