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.

抽象的癌症个体中骨髓源性抑制细胞（MDSC）的积累已成为一种逃避抗肿瘤免疫的主要机制，也是开发高效药物的主要障碍癌症免疫疗法。尽管它们与肿瘤诱导的免疫抑制具有不可否认的相关性，但目前尚无有效阻断癌症患者中 MDSC 免疫抑制活性的方法。因此，迫切需要抑制 MDSC 的新治疗策略。在整个拟议的研究中，我们的目标是确定基于抗体的 Notch 配体 Jagged1-2 阻断的机制荷瘤宿主功能性地将 MDSC 转化为启动抗肿瘤 T 细胞反应的骨髓亚群。这得到了重要的支持结果的支持，该结果表明，用人源化药物治疗荷瘤宿主识别人类和小鼠 Jagged1-2 (CTX014) 的阻断抗体可显着延迟肿瘤发生生长并将 MDSC 转化为细胞群，促进反应性 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） Jagged1-2 在癌细胞和/或肿瘤浸润性 MDSC 中的表达在抑制中发挥核心作用肿瘤中的保护性 T 细胞免疫； 2) 用抗 Jagged1-2 疗法治疗荷瘤小鼠对 MDSC 进行功能性重编程，克服肿瘤相关 T 细胞抑制，并提高有前途的癌症免疫疗法。为了测试这些假设，我们提出了以下具体目标：1) 确定癌细胞-Jagged1-2在MDSC诱导的肿瘤免疫抑制活性中的作用轴承主机； 2) 阐明导致肿瘤-MDSC和Jagged配体上调的机制了解 MDSC 表达的 Jagged1 对肿瘤诱导耐受的内源性影响； 3）测试预测 Jagged 对癌细胞和 MDSC 的联合抑制可克服肿瘤诱导的 T 细胞抑制并增强各种形式的免疫疗法的功效。完成这个高度创新和转化研究将阐明 Jagged1 和 2 作为 T 主要调节者的作用肿瘤中发生的细胞功能障碍为开发新的治疗方法铺平了道路对癌症患者的 MDSC 进行功能性重编程，有望预防和/或逆转肿瘤诱导 T 细胞耐受并提高有前景的癌症免疫疗法的功效。