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: 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
• 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

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.

持续向肿瘤微环境输送IL-12和GM-CSF诱导快速激活 预先存在的CD8+T效应细胞/记忆细胞，促进消除CD4+CD25+Foxp3+T抑制细胞 并导致在肿瘤引流淋巴结(TDLN)中启动次级CD8+T效应反应。 然而，肿瘤免疫抑制的逆转是短暂的，效应器的激活之后是戏剧性的 T-抑制细胞反弹，T-效应器恢复静止。再次刺激导致了这种强化 的调节反弹，并最终在治疗效果的丧失。最近的研究表明， CD8+T效应细胞启动和T抑制细胞反弹均由同一髓系树突状细胞介导 治疗后被招募到TDLN的细胞(DC)群体。更重要的是，需要干扰素？ 最初的免疫原性和随后的耐受性DC(TDC)表型的发展。这个 将在这一应用中检验的广泛假设是，干扰素驱动的免疫原性和耐受性 DC中的通路可以解偶联，选择性抑制产生耐受的通路将中和 体内平衡T抑制细胞反弹，导致肿瘤持久消退。为此，目标1的研究包括 旨在描述鲜为人知的控制干扰素驱动的免疫原性分化的机制 数据中心(IDC)至贸易发展局。更具体地说，选定的干扰素调节因子(IRF)在 阐明了IDC和TDC表型的差异，以确定可以作为目标的潜在检查点 用于选择性地阻断贸发局的发展和持久性。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来消除反调节进行了测试。 第一，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以及在AIM 1中确定的其他候选基因通过siRNA/GOLD靶向 纳米棒复合体和缓释细胞因子/小分子药物制剂，以阻断TDC功能。 其次，基于最近发现的T抑制细胞表型具有相当大的可塑性， 上述技术被用来通过Foxp3沉默和传递来重新编程反弹的T抑制细胞 TH1/TH17促进细胞因子的表达。在目标3中，上述方法的长期治疗潜力是 在两个临床相关的肿瘤模型中进行了研究。首先，利用外科转移模型来确定 局部消除T抑制细胞反弹是否会导致弥漫性疾病的增强根除 疾病。在第二个模型中，慢性免疫疗法在非霍奇金淋巴瘤长期治疗中的应用 可切除疾病是在一个先进的原发肿瘤模型中评估的。分子基础的阐明 治疗诱导的动态平衡反调节和识别潜在的调节检查点 可以靶向中和T抑制因子的反弹代表了一种新的范式，如果成功， 可以显著提高以免疫为基础的治疗的临床疗效。