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

摘要 在癌症患者中，髓系来源的抑制细胞(MDSC)的积累已经成为一种 抗肿瘤免疫逃避的主要机制和高效药物开发的主要障碍 癌症免疫疗法。尽管它们在肿瘤诱导的免疫抑制中具有不可否认的相关性，但有 目前尚无有效阻断癌症患者MDSC免疫抑制活性的方法。 因此，迫切需要新的治疗策略来抑制MDSC。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在 荷瘤宿主在功能上将MDSC转化为启动抗肿瘤T细胞反应的髓系亚群。 关键的支持结果支持了这一点，该结果表明，用人性化的 识别人和小鼠Jagged1-2(CTX014)的封闭抗体显著延迟肿瘤生长 MDSC的生长和转化为促进反应性CD8+T细胞渗透的细胞群 转化为肿瘤，提高了T细胞免疫疗法的疗效。因此，我们假设：1) Jagged1-2在肿瘤细胞和/或肿瘤浸润性MDSC中的表达在抑制中起中心作用 2)抗Jagged1-2治疗荷瘤小鼠 从功能上对MDSC进行重新编程，克服与肿瘤相关的T细胞抑制，并提高 前景看好的癌症免疫疗法。为了检验这些假设，我们提出了以下具体目标：1) 确定肿瘤细胞Jagged1-2在MDSC诱导的免疫抑制活性中的作用 2)阐明肿瘤-MDSC中锯齿状配体表达上调的机制； 了解MDSC表达的Jagged1在肿瘤诱导的耐受中的内源性作用；3)测试 预测肿瘤细胞和MDSC联合抑制锯齿状基因可克服肿瘤诱导的T细胞 抑制和提高各种形式的免疫疗法的疗效。完成这一高度 创新和翻译研究将阐明Jagged1和Jagged2作为T的主要调节因子的作用 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道路 对癌症患者的MDSC进行功能性重新编程，有望预防和/或逆转肿瘤- 诱导T细胞耐受，提高有希望的癌症免疫疗法的疗效。

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.