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：
8257492
负责人：
NEJAT K EGILMEZ
金额：
$ 29.92万
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 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8257492
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 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.

将 Interleukin-12 和 GM-CSF 持续递送至肿瘤微环境可诱导快速激活预先存在的 CD8+ T 效应细胞/记忆细胞，促进 CD4+ CD25+ Foxp3+ T 抑制细胞的消除并导致肿瘤引流淋巴结 (TDLN) 中次级 CD8+ T 效应器反应的启动。然而，肿瘤免疫抑制的逆转是短暂的，效应器激活之后会出现戏剧性的变化。 T 抑制细胞的反弹和 T 效应细胞静止的恢复导致强化。最近的研究表明，监管反弹并最终导致治疗效果的丧失。 CD8+ T 效应细胞启动和 T 抑制细胞反弹均由相同的骨髓树突介导治疗后招募到 TDLN 的细胞 (DC) 群体更重要的是，IFN¿被要求用于初始免疫原性和随后的耐受性 DC (tDC) 表型的发展。本申请中将测试的广泛假设是 IFN¿驱动的免疫原性和耐受性 DC 中的通路可以解偶联，并且选择性抑制致耐受性通路将中和稳态 T 抑制细胞反弹，导致肿瘤持久消退为此，Aim 1 研究正在进行。旨在描述控制 IFN 的鲜为人知的机制¿免疫原性驱动的分化 DC (iDC) 到 tDC 更具体地说，选定的干扰素调节因子 (IRF) 在阐明 iDC 和 tDC 表型的差异，以确定可靶向的潜在检查点在目标 2 中，有两种不同的策略旨在选择性阻断 tDC 的发展和持久性。测试了通过使用独特的体内大分子递送技术来废除反监管。首先，治疗后 tDC 分化和活性的潜在调节因子，包括 IRF-8、SOCS-1、IDO-1/2、 GCN-2 和 MyD88 以及目标 1 中确定的其他候选物通过 siRNA/gold 进行靶向纳米棒复合物和缓释细胞因子/小分子药物制剂可阻断 tDC 功能。其次，根据最近的研究结果表明 T 抑制细胞表型具有相当大的可塑性，上述技术用于通过 Foxp3 沉默和传递来重新编程反弹的 T 抑制细胞在目标 3 中，上述方法的长期治疗潜力是。首先，利用手术转移模型来确定两个临床相关的肿瘤模型。局部消除 T 抑制细胞反弹是否会导致增强根除播散性在第二个模型中，慢性免疫疗法在非疾病的长期管理中的应用。在先进的原发性肿瘤模型中评估可切除的疾病，阐明其分子基础。治疗引起的稳态反调节和潜在调节检查点的识别可以针对 T 抑制子反弹的中和代表一种新的范例，如果成功的话，可以显着提高免疫疗法的临床疗效。