The c-Rel Checkpoint for Immunosuppression and Immunotherapy

该研究项目的主要目标是描述一种新的免疫检查点， 开发一种新的免疫策略来治疗癌症。免疫治疗靶向 淋巴细胞检查点对治愈癌症有很大的希望。然而，大多数癌症 患者对这种形式的治疗没有反应。除了淋巴样细胞，髓样细胞 在控制对癌症的免疫力方面起着重要作用。是否存在骨髓检查点， 靶向治疗癌症的方法还没有很好地建立。骨髓源性抑制细胞（MDSC）是一种 新发现的对癌症重要的白细胞群。MDSC的消耗导致 显着增强小鼠的抗肿瘤免疫力，可能是癌症治疗成功的关键 人体免疫疗法尽管它们在癌症中的重要性，MDSC仍然是最小的 骨髓细胞的亚群。目前还不清楚是什么转录程序指定MDSC 分化;目前还不知道什么药物方法可以用于靶向MDSC， 癌症的治疗。这份资助申请的灵感来自于我们最近的发现， 因子c-Rel是人和鼠MDSC发育和/或功能所必需的，并且 c-Rel抑制剂可有效治疗小鼠癌症。该项目的目标是（i）阐明 c-Rel调节鼠和人MDSC的机制，以及（ii）建立 我们的c-Rel抑制剂用于治疗癌症的功效和作用机制。

The primary objectives of this research project are to characterize a new immune checkpoint and to develop a new immunotherapeutic strategy to treat cancer. Immunotherapy that targets lymphoid cell checkpoints holds great promise for curing cancer. However, a majority of cancer patients do not respond to this form of therapy. In addition to lymphoid cells, myeloid cells play essential roles in controlling immunity to cancer. Whether myeloid checkpoints exist that can be targeted to treat cancer is not well established. Myeloid-derived suppressor cells (MDSCs) are a newly identified population of leukocytes important for cancer. Depletion of MDSCs leads to markedly enhanced anti-tumor immunity in mice, and may be crucial for the success of cancer immunotherapy in humans. Despite their significance in cancer, MDSCs remain to be the least understood subset of myeloid cells. It is unclear what transcriptional program specifies MDSC differentiation; it is unknown what pharmaceutical approach can be used to target MDSCs for the treatment of cancer. This grant application is inspired by our recent discovery that the transcription factor c-Rel is required for both human and murine MDSC development and/or function, and that c-Rel inhibitors are effective for treating cancer in mice. The goals of this project are to (i) elucidate the mechanisms through which c-Rel regulates murine and human MDSCs, and (ii) establish the efficacy and the mechanisms of action of our c-Rel inhibitors for the treatment of cancer.