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

• 批准号: 8096730
• 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
• 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/8096730
• 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; public health relevance; response; small molecule; tumor; tumor eradication; tumor progression

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This proposal will define the molecular mechanisms underlying the homeostatic regulatory rebound that short-circuits therapy-induced antitumor cytotoxic cell activity. Delineation of how treatment itself leads to the mobilization of a regulatory counter-response is expected to reveal checkpoints that can be targeted for abrogation of the regulatory rebound. To this end, novel controlled-release formulations of siRNA, recombinant proteins and small molecule drugs are utilized in conjunction with therapy to target anticipated checkpoints and reprogram regulatory cells to achieve durable tumor regression.

描述（由申请人提供）：将白细胞介素-12和GM-CSF持续递送到肿瘤微环境可诱导预先存在的CD8+ t效应细胞/记忆细胞的快速激活，促进CD4+ CD25+ Foxp3+ t抑制细胞的消除，并导致肿瘤引流淋巴结（TDLN）中继发CD8+ t效应反应的启动。然而，肿瘤免疫抑制的逆转是短暂的，效应激活之后是t抑制细胞的急剧反弹和t效应静止的恢复。再刺激导致调节反弹的增强，最终导致治疗效果的丧失。最近的研究表明，CD8+ t效应细胞启动和t抑制细胞反弹都是由治疗后被招募到TDLN的相同骨髓树突状细胞（DC）群介导的。更重要的是，IFN？对于初始免疫原性和随后的耐受性DC （tDC）表型的发展都是必需的。在这个应用中要测试的一个宽泛的假设是IFN？DC中驱动的免疫原和耐受性途径可以解耦，选择性抑制耐受性途径将中和稳态t抑制细胞反弹，从而导致持久的肿瘤消退。为此，Aim 1研究旨在描述鲜为人知的控制IFN的机制。免疫原性DC （iDC）向tDC的驱动分化。更具体地说，选定的干扰素调节因子（irf）在iDC和tDC表型分化中的具体作用被阐明，以确定潜在的检查点，这些检查点可以选择性阻断tDC的发展和持续。在目标2中，通过使用独特的体内大分子递送技术，测试了两种不同的策略，旨在废除反调节。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Aim 1中确定的其他候选因子，通过siRNA/金纳米棒复合物和缓释细胞因子/小分子药物制剂靶向阻断tDC功能。其次，基于最近的研究发现，t抑制细胞表型具有相当大的可塑性，上述技术被用于通过Foxp3沉默和传递TH1/ th17促进细胞因子来重新编程反弹的t抑制细胞。在Aim 3中，上述方法的长期治疗潜力在两种临床相关肿瘤模型中进行了研究。首先，利用手术转移模型来确定局部消除t抑制细胞反弹是否会增强对播散性疾病的根除。在第二个模型中，慢性免疫治疗在不可切除疾病的长期治疗中的效用在一个晚期原发性肿瘤模型中被评估。阐明治疗诱导的体内平衡反调节的分子基础和确定潜在的调节检查点，可以靶向中和t抑制因子反弹，这代表了一种新的范式，如果成功，可以显著提高免疫治疗的临床疗效。