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: 9130120
• 负责人: DAVID P. CARBONE
• 金额: $ 31.43万
• 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/9130120
• 关键词: 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; Health; 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; 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; improved outcome; inhibitor/antagonist; mouse model; notch protein; novel; novel therapeutic intervention; novel therapeutics; preclinical study; prognostic; prognostic assays; response; targeted treatment; 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）：在癌症治疗中将免疫疗法与靶向疗法相结合提出了一种新的组合策略，其中两种不同模式的互补作用模式表明了治疗协同作用的迷人可能性。强 一系列证据表明，抗肿瘤免疫对于常规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应答，将靶向疗法的令人印象深刻的临床应答巩固为持久的缓解。拟议的研究是基于我们已发表的和初步的数据，这些数据定义了一种新的Notch介导的癌症相关免疫抑制分子机制，结合候选的全身治疗方法，克服了这种免疫抑制。我们揭示了肿瘤和下调造血区室中的Delta样（DLL）Notch配体的表达，并且由此产生的Notch活化降低导致T细胞缺陷。DLL 1介导的Notch信号传导的遗传或治疗增强足以纠正肿瘤诱导的T淋巴细胞分化缺陷，改善T细胞应答和记忆，并产生显著的肿瘤抑制。我们在小鼠肿瘤模型中产生并测试了原型治疗试剂，可溶性成簇（多价）DLL 1，其证明了免疫和治疗功效。厄洛替尼是一种表皮生长因子受体（EGFR）抑制剂，在治疗非小细胞肺癌（NSCLC）中显示出显著的临床疗效和生存益处，但疾病复发仍然是一个关键的突出问题。我们假设免疫微环境中足够的Notch信号传导对于诱导抗肿瘤免疫至关重要，并且Notch信号传导的配体特异性药理学增强可以通过诱导稳健和持久的抗肿瘤免疫应答来显著改善EGFR靶向治疗后的无进展生存期。我们打算在以下具体目标中测试这一想法：1）确定树突状细胞中Notch配体表达在调节抗肿瘤免疫应答中的作用。2)评估抗EGFR靶向治疗与EGFR增强的DLL 1/Notch信号传导和多价DLL 1拯救缺陷性T细胞、诱导持续免疫应答和持久缓解的能力的组合的临床疗效。3)探讨Notch系统在非小细胞肺癌靶向治疗后Th细胞分化调控及诱导长期缓解中的意义。我们计划专注于上述目标，以实现对Notch，DLL 1和其他Notch配体在抗肿瘤免疫中的作用的分子理解，并评估该系统的调节和评估可能提供的治疗和预后潜力。拟议的临床前研究将为我们提供线索，使这些发现转化为临床相关的治疗和预后测定。