Integrating innate and adaptive immunity in cancer therapy

将先天免疫和适应性免疫整合到癌症治疗中

基本信息

批准号：
8462112
负责人：
NEJAT K EGILMEZ
金额：
$ 28.13万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-05-21 至 2013-12-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8462112
关键词：
Back CD8B1 gene Cell physiology Cells Chronic Complex Dendritic Cells Development Disease Drug Formulations Effector Cell Event Funding Goals Gold Granulocyte-Macrophage Colony-Stimulating Factor IFN consensus sequence binding protein IL2RA gene Immune Immunosuppression Immunotherapy Interferons Interleukin-12 Local Therapy Mediating Memory Modeling Molecular Molecular Analysis Monitor Mus Myelogenous Natural Immunity Natural Killer Cells Neoplasm Metastasis Operative Surgical Procedures Pathway interactions Pharmaceutical Preparations Phenotype Population Primary Neoplasm Recombinant Cytokines Recombinant Proteins Recruitment Activity Regulation Regulatory Pathway Research Research Design Resectable Role Small Interfering RNA Suppressor-Effector T-Lymphocytes T-Lymphocyte Technology Testing Treatment Efficacy Work adaptive immunity base cancer therapy clinical efficacy clinically relevant controlled release cytokine immunogenic improved in vivo inhibitor/antagonist lymph nodes macromolecule nanorod novel paracrine programs response small molecule tumor tumor eradication tumor microenvironment tumor progression

项目摘要

Sustained delivery of Interleukin-12 and GM-CSF to the tumor microenvironment induces rapid activation of pre-existing CD8+ Teffector/memory cells, promotes elimination of CD4+ CD25+ Foxp3+ T-suppressor cells and results in the priming of a secondary CD8+ T-effector response in the tumor-draining lymph nodes (TDLN). However, reversal of tumor immune suppression is transient and effector activation is followed by a dramatic rebound of T-suppressor cells and return of T-effector quiescence. Re-stimulation results in the intensification of the regulatory rebound and ultimately, in the loss of therapeutic efficacy. Recent work demonstrated that both CD8+ T-effector cell priming and T-suppressor cell rebound were mediated by the same myeloid Dendritic cell (DC) population that was recruited to the TDLN following treatment. More importantly, IFN¿ was required for the development of both the initial immunogenic and the subsequent tolerogenic DC (tDC) phenotype. The broad hypothesis that will be tested in this application is that IFN¿-driven immunogenic and tolerogenic pathways in DC can be uncoupled and that selective inhibition of the tolerogenic pathway will neutralize the homeostatic T-suppressor cell rebound, resulting in durable tumor regression. To this end, Aim 1 studies are designed to delineate the little-known mechanisms controlling the IFN¿-driven differentiation of immunogenic DC (iDC) to tDC. More specifically, the specific roles of selected interferon regulatory factors (IRFs) in the differentiation of iDC and tDC phenotypes are elucidated to identify potential checkpoints that can be targeted for selective blocking of tDC development and persistence. In Aim 2, two different strategies aimed at abrogating counter-regulation via the use of unique in vivo macromolecule delivery technologies are tested. First, potential regulators of post-therapy tDC differentiation and activity, including IRF-8, SOCS-1, IDO-1/2, GCN-2 and MyD88 as well as additional candidates that are identified in Aim 1, are targeted via siRNA/gold nanorod complexes and sustained-release cytokine/small molecule drug formulations to block tDC function. Second, based on recent findings demonstrating considerable plasticity in T-suppressor cell phenotype, the above technologies are utilized to re-program rebounding T-suppressor cells via Foxp3 silencing and delivery of TH1/TH17-promoting cytokines. In Aim 3, the long-term curative potential of the above approach is investigated in two clinically-relevant tumor models. First, a surgical metastasis model is utilized to determine whether local abrogation of the T-suppressor cell rebound will result in enhanced eradication of disseminated disease. In the second model, the utility of chronic immune therapy in long-term management of non- resectable disease is evaluated in an advanced primary tumor model. Elucidation of the molecular basis of treatment-induced homeostatic counter-regulation and identification of potential regulatory checkpoints that can be targeted for neutralization of the T-suppressor rebound represents a new paradigm, which if successful, can significantly improve clinical efficacy of immune-based therapies.

持续将白介素-12和GM-CSF递送到肿瘤微环境中会诱导快速激活预先存在的CD8+ TEFFECTOR/存储单元，促进CD4+ CD25+ FOXP3+ T-Suppressor细胞的消除并导致在肿瘤淋巴结（TDLN）中启动次级CD8+ T-效应器反应。然而，肿瘤免疫抑制的逆转是短暂的，效应子激活之后是戏剧性的重新刺激导致强化监管反弹，最终在丧失治疗效率方面。最近的工作表明 CD8+ T-效应器细胞启动和T-抑制细胞的反弹均由相同的髓样树突状介导治疗后招募到TDLN的细胞（DC）人群。更重要的是，需要为了发展初始免疫原性和随后的耐受性DC（TDC）表型。在此应用中将测试的广泛假设是IFN®驱动的免疫原性和耐受性 DC中的途径可以取消耦合，并且选择性抑制耐受性途径将中和稳态T-抑制细胞反弹，导致耐用的肿瘤回归。为此，目标1研究是旨在描述控制IFN®驱动的免疫原性分化的鲜为人知的机制 DC（IDC）至TDC。更具体地说，选定的干扰素调节因子（IRF）在 IDC和TDC表型的区分被阐明，以识别可以针对的潜在检查点用于选择性阻止TDC的发展和持久性。在AIM 2中，针对的两种不同的策略测试通过使用独特的体内大分子递送技术来进行反调节。首先，治疗后TDC分化和活动的潜在调节剂，包括IRF-8，SOCS-1，IDO-1/2， GCN-2和MYD88以及AIM 1中确定的其他候选者是针对通过siRNA/GOLD的纳米棒复合物和持续释放的细胞因子/小分子药物配方可阻止TDC功能。第二，根据最近的发现，表明T-抑制细胞表型中的可塑性很大，上面的技术用于通过FOXP3沉默和交付来重新编程T-suppressor细胞 Th1/Th17促进细胞因子。在AIM 3中，上述方法的长期治愈潜力是在两个临床上与临床相关的肿瘤模型中进行了研究。首先，使用手术转移模型来确定局部废除T-抑制器细胞反弹是否会增强散布疾病。在第二个模型中，慢性免疫治疗在长期管理非 - 在晚期原发性肿瘤模型中评估可切除疾病。阐明分子基础的治疗引起的稳态反调节和对潜在调节检查点的识别可以针对T-suppressor反弹的神经化的目标是一个新的范式，如果成功的话，可以显着提高基于免疫的疗法的临床效率。