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: 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
• 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

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.

持续递送白细胞介素-12和GM-CSF至肿瘤微环境诱导肿瘤细胞因子的快速活化。 预先存在的CD 8 + T效应/记忆细胞，促进CD 4 + CD 25 + Foxp 3 + T抑制细胞的消除 并导致在肿瘤引流淋巴结（TDLN）中引发继发性CD 8 + T效应子应答。 然而，肿瘤免疫抑制的逆转是短暂的，效应子激活之后是显著的免疫抑制。 T抑制细胞的反弹和T效应细胞静止的恢复。再刺激导致了 监管反弹，并最终导致治疗效果的丧失。最近的研究表明， CD 8 + T效应细胞的启动和T抑制细胞的反弹都是由相同的髓样树突状细胞介导的。 细胞（DC）群体，其在治疗后被募集到TDLN。更重要的是， 用于形成初始免疫原性和随后的致耐受性DC（tDC）表型。的 在本申请中将检验的一个广泛假设是IFN γ驱动的免疫原性和致耐受性 DC中的耐受性途径可以解偶联，并且耐受性途径的选择性抑制将中和DC中的耐受性途径。 稳态T抑制细胞反弹，导致持久的肿瘤消退。为此，目标1研究是 旨在描述控制IFN-γ驱动的免疫原性分化的鲜为人知的机制， DC（iDC）到tDC。更具体地说，选择的干扰素调节因子（IRF）的具体作用， 阐明了iDC和tDC表型的区别，以鉴定可以靶向的潜在检查点 用于选择性阻断tDC的发展和持久性。在目标2中，两种不同的战略旨在 通过使用独特的体内大分子递送技术消除反调节。 首先，治疗后tDC分化和活性的潜在调节剂，包括IRF-8，SOCS-1，IDO-1/2， 通过siRNA/gold靶向GCN-2和MyD 88以及目标1中鉴定的其他候选物 纳米棒复合物和持续释放的细胞因子/小分子药物制剂来阻断tDC功能。 其次，基于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Foxp 3沉默和递送来重新编程反弹的T抑制细胞 TH 1/TH 17-促进细胞因子。在目标3中，上述方法的长期治愈潜力是 在两个临床相关的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导致增强的播散性 疾病在第二个模型中，慢性免疫治疗在非免疫性疾病的长期管理中的效用是： 在晚期原发性肿瘤模型中评价可切除的疾病。分子基础的阐明 治疗诱导的稳态反调节和鉴定潜在的调节检查点， 可以有针对性地中和T抑制反弹代表了一种新的范式，如果成功， 可显著提高免疫疗法的临床疗效。