WEE1 inhibition and tumor immunity

WEE1抑制和肿瘤免疫

基本信息

批准号：
10241248
负责人：
Bin Zhang
金额：
$ 42万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241248
关键词：
Ablation Affect Animal Model CD8-Positive T-Lymphocytes CD8B1 gene CDC2 gene Cancer cell line Cell Cycle Cell Cycle Checkpoint Cell Cycle Regulation Cell Differentiation process Cell Survival Cells Clinic Combined Modality Therapy Cyclin B DNA Repair Data Development Environment Gatekeeping Generations Genetic Genetic Transcription Growth Immune Immune Tolerance Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Impairment In Vitro Infiltration Interferon Type II Knock-out Knowledge Link Malignant Neoplasms Mediating Molecular PD-1 blockade PD-L1 blockade Pharmacology Phosphorylation Phosphotransferases Pilot Projects Production Pyrimidine Reagent Regulation Regulatory T-Lymphocyte Resistance Role Signal Transduction Small Interfering RNA T-Lymphocyte Testing Therapeutic Treatment Efficacy Tumor Burden Tumor Immunity Tumor Promotion Tumor Suppression Up-Regulation Work anti-CTLA-4 therapy anti-PD-1 anti-PD-1/PD-L1 base cancer cell cancer immunotherapeutics cancer immunotherapy cancer type cellular targeting chemokine clinical development clinically relevant combinatorial cytotoxic defined contribution design effector T cell immune checkpoint blockade immunoregulation inhibitor/antagonist insight neoplastic cell novel overexpression preclinical study programmed cell death ligand 1 programmed cell death protein 1 recruit small molecule inhibitor targeted treatment therapeutic target transcription factor tumor tumor growth tumor microenvironment tumorigenic

项目摘要

Project summary Tumors employ a number of mechanisms to promote immune escape, including the infiltration of different immunosuppressive cells in the tumor microenvironment such as T-regulatory cells (Treg). However, the specific signals within tumor cells that regulate the recruitment of Tregs, giving rise to tumor-induced immunosuppression, remain elusive. Based on our new preliminary data, we hypothesize that WEE1, an important regulator for cell cycle checkpoints, maintains an immunosuppressive and pro- tumorigenic microenvironment, and suppressing WEE1 activity, including via a clinically relevant WEE1 inhibitor, may be therapeutically beneficial by boosting immune-mediated tumor clearance. This proposal seeks to characterize the novel regulatory perspectives of WEE1-mediated crosstalk between tumor cells and host immune cells that should significantly forward the field. Specifically, this project is searching for the molecular mechanisms of WEE1-mediated Treg regulation and development of new effective combinatorial strategies. Our work will thus identify an unappreciated role of WEE1 inhibition in reversing tumor-induced immune suppression.

项目概要肿瘤采用多种机制来促进免疫逃逸，包括肿瘤微环境中不同免疫抑制细胞的浸润，例如 T 调节细胞（Treg）。然而，肿瘤细胞内调节的特定信号 Tregs 的募集，引起肿瘤诱导的免疫抑制，仍然存在难以捉摸。根据我们新的初步数据，我们假设 WEE1，一个重要的细胞周期检查点的调节器，维持免疫抑制和亲致瘤微环境，并抑制 WEE1 活性，包括通过临床相关的 WEE1 抑制剂，可能通过增强免疫介导而具有治疗益处肿瘤清除。该提案旨在描述新颖的监管观点 WEE1介导的肿瘤细胞和宿主免疫细胞之间的串扰应该显着向前推进该领域。具体来说，该项目正在寻找分子 WEE1介导的Treg调节机制和新有效的开发组合策略。因此，我们的工作将确定 WEE1 未被重视的作用抑制逆转肿瘤诱导的免疫抑制。