The c-Rel Checkpoint for Immunosuppression and Immunotherapy

这项研究项目的主要目标是描述一种新的免疫检查点和 开发一种新的免疫治疗策略来治疗癌症。针对目标的免疫疗法 淋巴细胞检查站为治愈癌症带来了巨大的希望。然而，大多数癌症 患者对这种形式的治疗没有反应。除了淋巴细胞外，髓系细胞还扮演着 在控制癌症免疫力方面的重要作用。是否存在髓系检查点 有针对性地治疗癌症还没有得到很好的证实。髓系来源的抑制细胞(MDSC)是一种 新发现的对癌症有重要作用的白细胞群。MDSCs的枯竭导致 显著增强小鼠的抗肿瘤免疫能力，这可能是癌症成功的关键 人类的免疫疗法。尽管MDSCs在癌症中具有重要意义，但它仍然是最不重要的 了解髓系细胞的亚群。目前还不清楚MDSC的转录程序是什么 目前尚不清楚可以使用什么药物方法来靶向MDSCs治疗 癌症的治疗。这项拨款申请的灵感来自我们最近的发现，即 人和小鼠MDSC的发育和/或功能都需要因子c-Rel，并且 C-Rel抑制剂对治疗小鼠癌症有效。本项目的目标是(I)阐明 C-Rel调节小鼠和人MDSCs的机制，以及(Ii)建立 我们的c-rel抑制剂治疗癌症的疗效和作用机制。

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.