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）：将免疫治疗与靶向治疗结合起来，在癌症治疗中提出了一种新的组合策略，其中两种不同方式的互补作用模式表明了治疗协同作用的迷人可能性。强大的