Notch ligands in regulation of anti-cancer immunity

Notch配体在抗癌免疫调节中的作用

• 批准号: 8743193
• 负责人: DAVID P. CARBONE
• 金额: $ 30.48万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8743193
• 关键词: Biological Assay; Cancer Patient; Cell Differentiation Induction; Cell physiology; Cells; Cellular Immunity; Clinical; Data; Defect; Dendritic Cells; Disease; Disease remission; Effector Cell; Epidermal Growth Factor Receptor; Erlotinib; Evaluation; Gene Expression Profile; Genes; Genetic; Genetic Engineering; Hematopoiesis; Hematopoietic; Human; ITGAX gene; Immune; Immune response; Immunity; Immunosuppression; Immunotherapy; Investigation; Knockout Mice; Ligands; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Memory; Modality; Modeling; Molecular; Mus; Mutant Strains Mice; Non-Small-Cell Lung Carcinoma; Notch Signaling Pathway; Oncogenes; Outcome; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Blood Mononuclear Cell; Predictive Value; Prevalence; Progression-Free Survivals; Publishing; Reagent; Recurrence; Regulation; Regulatory T-Lymphocyte; Relapse; Research; Role; Signal Transduction; Specific qualifier value; System; T cell differentiation; T cell response; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Translating; Translations; Treatment Efficacy; Tumor Immunity; base; cancer therapy; clinical efficacy; clinically relevant; clinically significant; combinatorial; fascinate; improved; inhibitor/antagonist; mouse model; notch protein; novel; novel therapeutic intervention; novel therapeutics; preclinical study; prognostic; public health relevance; response; tumor; tumor growth

DESCRIPTION (provided by applicant): Integrating immunotherapy with targeted therapies in cancer treatment presents a novel combinatorial strategy where complementary modes of action of two distinct modalities suggest fascinating possibilities for therapeutic synergy. Strong line of evidence suggests that anti-tumor immunity is critical for clinical responses toward conventional and pathway-targeted cancer treatments. Immunotherapies may serve to consolidate the impressive clinical responses from targeted therapies into durable remissions via induction of long-lasting immune responses. The proposed research is based on our published and preliminary our data that define a novel Notch-mediated molecular mechanism of cancer-associated immunosuppression, combined with candidate systemic therapeutics, which overcomes this immunosuppression. We revealed that tumors and down-regulates expression of Delta-like (DLL) Notch ligand in the hematopoietic compartment, and the resulting decreased Notch activation leads to defects in T cells. Genetic or therapeutic enhancement of DLL1- mediated Notch signaling was sufficient to correct tumor-induced defects in T lymphocyte differentiation, improve T cell responses and memory, and produce significant tumor inhibition. We generated and tested in mouse tumor models a prototypic therapeutic reagent, soluble clustered (multivalent) DLL1, that demonstrated immune and therapeutic efficacy. Erlotinib, an inhibitor of EGF receptor (EGFR), has shown significant clinical responses and survival benefit in the treatment of in Non-Small Cell Lung Cancer (NSCLC), however disease recurrence remains a key outstanding problem. We hypothesize that adequate Notch signaling in the immune microenvironment is crucial for the induction of anti-tumor immunity and that ligand-specific pharmacological enhancement of Notch signaling can be exploited to significantly improve progression-free survival after EGFR-targeted therapy via induction of robust and long-lasting anti-tumor immune responses. We intend to test this idea in the following specific aims: 1) Determine the roles of Notch ligand expression in dendritic cells in the regulation of anti-tumor immune responses. 2) Evaluate the clinical efficacy of combination of anti-EGFR targeted therapy with pharmacologically enhanced DLL1/Notch signaling and the ability of multivalent DLL1 to rescues defective T cells, induce sustained immune responses, and durable remission. 3) Evaluate significance of Notch system in regulation of Th cell differentiation and induction of long-lasting remission in NSCLC patients after targeted therapy. We plan to focus on the above aims to achieve a molecular understanding of the role of Notch, DLL1 and other Notch ligands in anti-tumor immunity and to evaluate the therapeutic and prognostic potential that modulation and evaluation of this system could offer. The proposed pre-clinical studies will give us leads to enable the translation of these findings into clinically relevant therapeutics and prognostic assays.

描述（由申请人提供）：将免疫疗法与癌症治疗中的靶向疗法整合起来提出了一种新型的组合策略，其中互补的两种不同方式的互补作用模式表明治疗协同作用令人着迷。强的 证据线表明，抗肿瘤免疫对于对传统和途径靶向癌症治疗的临床反应至关重要。免疫疗法可以通过诱导持久的免疫反应来巩固目标疗法的令人印象深刻的临床反应，从而巩固持久的减免。拟议的研究基于我们发布的和初步的数据，该数据定义了一种新型的Notch介导的癌症相关免疫抑制的分子机制，并结合了候选全身治疗剂，从而克服了这种免疫抑制。我们透露，肿瘤和下调造血区室中三角形（DLL）缺口配体的表达，所得的降低凹口激活导致T细胞中的缺陷。 DLL1介导的Notch信号的遗传或治疗性增强足以纠正T淋巴细胞分化中肿瘤诱导的缺陷，改善T细胞反应和记忆力，并产生明显的肿瘤抑制作用。我们在小鼠肿瘤模型中生成并测试了一种原型治疗试剂，可溶性聚类（多价）DLL1，该试剂表现出了免疫和治疗功效。 EGF受体（EGFR）抑制剂Erlotinib在非小细胞肺癌（NSCLC）治疗中显示出显着的临床反应和生存益处，但是疾病复发仍然是一个关键的关键问题。我们假设免疫微环境中足够的缺口信号对于诱导抗肿瘤免疫力至关重要，并且可以利用配体特异性的Notch信号的药理增强，可以显着提高EGFR靶向的无靶向治疗，这是通过EGFR靶向的无性抗性和长期抗抗耐受性的抗反效果，可以显着提高无态度的生存治疗。我们打算在以下特定目的中测试这一想法：1）确定凹口配体在树突状细胞中的作用在抗肿瘤免疫反应调节中。 2）评估抗EGFR靶向治疗与药理增强的DLL1/NOTCH信号的组合以及多价DLL1挽救缺陷T细胞的能力，诱导持续的免疫反应和持久缓解的能力。 3）评估Notch系统在靶向治疗后NSCLC患者中TH细胞分化和持续缓解诱导的显着性。我们计划专注于上述旨在对Notch，DLL1和其他缺口配体在抗肿瘤免疫中的作用有了分子的了解，并评估该系统的调节和评估可以提供的治疗和预后潜力。拟议的临床前研究将使我们能够将这些发现转化为临床相关的治疗剂和预后测定。