Functional reprogramming of tumor-MDSC through antibody-based therapies targeting Notch ligands

通过针对 Notch 配体的抗体疗法对肿瘤 MDSC 进行功能重编程

基本信息

批准号：
10406931
负责人：
Paulo Cesar Rodriguez
金额：
$ 38.56万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-06 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10406931
关键词：
Antibodies Antibody Therapy Antitumor Response Blocking Antibodies CD8-Positive T-Lymphocytes Cancer Patient Cell Death Cell physiology Cells Cellular immunotherapy DNA Data Development Functional disorder Goals Human IRF3 gene Immune Immunity Immunosuppression Immunotherapy Impairment Individual Infiltration Joints Ligands Link Malignant Neoplasms Mediator of activation protein Monoclonal Antibodies Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Pathway interactions Patients Play Population Public Health Regulation Research Resistance Role Signal Transduction Solid Neoplasm Sting Injury T cell response T-Lymphocyte Testing Time Translational Research Treatment Efficacy Tumor Immunity Up-Regulation base cancer cell cancer immunotherapy cell growth checkpoint therapy cross-species transmission cytotoxicity design experimental study humanized antibody immunogenic immunoregulation innovation insight neoplastic cell notch protein novel strategies novel therapeutic intervention novel therapeutics prevent targeted treatment treatment strategy tumor tumor growth tumor-immune system interactions

项目摘要

Abstract The accumulation of Myeloid-derived suppressor cells (MDSC) in individuals with cancer has emerged as a major mechanism of evasion of anti-tumor immunity and a primary obstacle to the development of efficient cancer immunotherapies. Despite their undeniable relevance in tumor-induced immune suppression, there are no current approaches to effectively block the immunosuppressive activity of MDSC in patients with cancer. Thus, novel therapeutic strategies to inhibit MDSC are urgently needed. Throughout the proposed research, we aim to determine the mechanisms by which the antibody-based blockade of the Notch ligands Jagged1-2 in tumor-bearing hosts functionally transforms MDSC into myeloid subsets that prime anti-tumor T cell responses. This is supported by crucial supporting results showing that treatment of tumor-bearing hosts with a humanized blocking antibody that recognizes the human and murine Jagged1-2 (CTX014) significantly delayed tumor growth and transformed MDSC into cellular populations that promoted the infiltration of reactive CD8+ T cells into tumors and enhanced the efficacy of T cell-based immunotherapy. Therefore, we hypothesize that: 1) The expression of Jagged1-2 in cancer cells and/or tumor-infiltrating MDSC plays a central role in the suppression of protective T cell immunity in tumors; and 2) Treatment of tumor-bearing mice with anti-Jagged1-2 therapy functionally reprograms MDSC, overcomes tumor-related T cell suppression, and increases the efficacy of promising cancer immunotherapies. To test these postulates, we proposed the following Specific Aims: 1) Determine the role of cancer cell-Jagged1-2 in the immunosuppressive activity induced by MDSC in tumor- bearing hosts; 2) Elucidate the mechanisms leading to the upregulation of Jagged ligands in tumor-MDSC and understand the endogenous effects of MDSC-expressed Jagged1 in tumor-induced tolerance; 3) Test the prediction that the combined inhibition of Jagged in cancer cells and MDSC overcomes tumor-induced T cell suppression and enhances the efficacy of various forms of immunotherapy. Completion of this highly innovative and translational research will elucidate the role of Jagged1 and 2 as primary mediators for the T cell dysfunction occurring in tumors and pave the way for the development of a novel therapeutic approach to functionally reprogram MDSC in patients with cancer, which is expected to prevent and/or reverse tumor- induced T cell tolerance and boost the efficacy of promising forms of cancer immunotherapy.

抽象的癌症患者中髓样衍生的抑制细胞（MDSC）的积累已成为一种逃避抗肿瘤免疫力的主要机制和有效发展的主要障碍癌症免疫疗法。尽管它们在肿瘤诱导的免疫抑制中的相关性不可否认，但仍有目前没有有效阻止MDSC在癌症患者中的免疫抑制活性的方法。因此，迫切需要抑制MDSC的新型治疗策略。在整个拟议的研究中，我们旨在确定基于抗体的凹槽配体jagged1-2的机制含有肿瘤的宿主在功能上将MDSC转化为主要抗肿瘤T细胞反应的髓样子集。这是由至关重要的支持结果支持的，表明用人源化治疗承重肿瘤的宿主识别人和鼠锯齿状1-2（CTX014）的阻塞抗体显着延迟了肿瘤生长并将MDSC转化为细胞种群，促进了反应性CD8+ T细胞的浸润进入肿瘤并增强基于T细胞的免疫疗法的功效。因此，我们假设：1）在癌细胞中锯齿状1-2的表达和/或肿瘤浸润的MDSC在抑制中起着核心作用肿瘤中的保护性T细胞免疫； 2）用抗果冻1-2治疗肿瘤的小鼠在功能上重新编程MDSC，克服了与肿瘤相关的T细胞抑制，并提高了有希望的癌症免疫疗法。为了测试这些假设，我们提出了以下特定目的：1）确定癌细胞杂点1-2在MDSC在肿瘤中诱导的免疫抑制活性中的作用轴承主持人； 2）阐明导致肿瘤MDSC中锯齿状配体上调的机制了解MDSC表达的JAGGED1在肿瘤诱导的耐受性中的内源性； 3）测试预测癌细胞和MDSC中锯齿状抑制的联合抑制克服了肿瘤诱导的T细胞抑制和增强各种形式的免疫疗法的功效。完成此功能创新和转化研究将阐明Jagged1和2作为T的主要介体的作用细胞功能障碍发生在肿瘤中，为开发一种新型治疗方法铺平了道路从功能上重新编程的癌症患者的MDSC，预计将预防和/或反向肿瘤 - 诱导的T细胞耐受性并提高了有前途的癌症免疫疗法的功效。