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

• 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
• 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

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.

摘要 骨髓来源的抑制细胞（MDSC）在癌症患者中的积累已经成为一个重要的因素。 逃避抗肿瘤免疫的主要机制和有效的发展的主要障碍 癌症免疫疗法尽管它们在肿瘤诱导的免疫抑制中不可否认的相关性， 目前没有有效阻断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的新的治疗策略。在整个拟议的研究中， 我们的目的是确定Notch配体Jagged 1 -2的基于抗体的阻断机制， 荷瘤宿主在功能上将MDSC转化为引发抗肿瘤T细胞应答的骨髓亚群。 这得到了关键的支持性结果的支持，这些结果表明，用人源化的抗肿瘤药物治疗荷瘤宿主是有效的。 识别人和鼠Jagged 1 -2的阻断抗体（CTX 014）显著延迟了肿瘤的发生。 生长并将MDSC转化为促进反应性CD 8 + T细胞浸润的细胞群 并增强了基于T细胞的免疫疗法的功效。因此，我们假设：1） 癌细胞和/或肿瘤浸润性MDSC中Jagged 1 -2的表达在抑制肿瘤生长中起着重要作用。 保护性T细胞免疫在肿瘤中的作用;和2）用抗Jagged 1 -2疗法治疗荷瘤小鼠 在功能上重新编程MDSC，克服肿瘤相关的T细胞抑制，并增加 癌症免疫疗法的前景。为了验证这些假设，我们提出了以下具体目标：1） 确定癌细胞Jagged 1 -2在MDSC诱导的肿瘤免疫抑制活性中的作用- 2）阐明导致肿瘤-MDSC中Jagged配体上调的机制， 了解MDSC表达的Jagged 1在肿瘤诱导的耐受中的内源性作用; 3）检测MDSC表达的Jagged 1在肿瘤诱导的耐受中的作用。 预测癌细胞和MDSC中Jagged的联合抑制克服了肿瘤诱导的T细胞 抑制并增强各种形式的免疫疗法的功效。完成这一高度 创新和转化研究将阐明Jagged 1和2作为T细胞的主要介导者的作用， 肿瘤中发生的细胞功能障碍，并为开发一种新的治疗方法铺平了道路， 在癌症患者中对MDSC进行功能性重编程，预期可预防和/或逆转肿瘤- 诱导T细胞耐受性，并提高有希望的癌症免疫疗法形式的功效。