The c-Rel Checkpoint for Immunosuppression and Immunotherapy

免疫抑制和免疫治疗的 c-Rel 检查点

基本信息

批准号：
10338110
负责人：
WARREN S PEAR
金额：
$ 50.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-11 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338110
关键词：
Antineoplastic Agents Applications Grants Biochemical Blood Cancer Patient Cell Differentiation process Cell physiology Collaborations Combined Modality Therapy Complex Development Disease Drug Targeting Effector Cell Elements Family Genes Genetic Genetic Transcription Genomic approach Goals Growth Heterogeneity Human Immune checkpoint inhibitor Immunity Immunosuppression Immunotherapeutic agent Immunotherapy Individual Inflammatory Knock-out Knowledge Leukocytes Lymphoid Cell Lymphoma Malignant Neoplasms Malignant lymphoid neoplasm Mediating Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nature Neoplasm Metastasis Nuclear Patients Pharmacologic Substance Pharmacotherapy Play Population Research Project Grants Risk Factors Role STAT3 gene Specific qualifier value Spleen Suppressor-Effector T-Lymphocytes Testing Tumor Immunity Tumor Suppressor Proteins anti-PD1 antibodies anti-cancer antitumor effect base cancer immunotherapy cancer therapy chromatin remodeling clinical practice detector factor C genetic signature genomic locus immune checkpoint inhibitor member monocyte neoplastic cell neutrophil novel progenitor programmed cell death protein 1 programs single-cell RNA sequencing small molecule inhibitor success theories transcription factor tumor tumor growth tumorigenesis

项目摘要

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.

该研究项目的主要目标是表征一个新的免疫检查点和制定一种新的免疫治疗策略来治疗癌症。靶向的免疫疗法淋巴样细胞检查点对治愈癌症有很大的希望。但是，大多数癌症患者对这种形式的治疗没有反应。除了淋巴样细胞外，髓样细胞发挥作用控制对癌症免疫的重要作用。是否存在髓样检查点针对治疗癌症的目标尚未确定。髓样衍生的抑制细胞（MDSC）是一个新确定的白细胞对癌症很重要。 MDSC的耗竭导致小鼠的抗肿瘤免疫明显增强，可能对癌症的成功至关重要人类的免疫疗法。尽管它们在癌症中具有重要意义，但MDSC仍然是最少的理解髓样细胞的子集。目前尚不清楚哪个转录程序指定MDSC 分化；尚不清楚哪种药物可以用于针对MDSC的MDSC 癌症的治疗。该赠款申请的灵感来自我们最近发现的转录人类和鼠MDSC的开发和/或功能都需要C-Rel因子C-Rel，并且 C-REL抑制剂可有效治疗小鼠的癌症。该项目的目标是（i）阐明 C-Rel调节鼠和人类MDSC的机制，以及（ii）建立我们的C-Rel抑制剂对癌症治疗的功效和作用机制。