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WEE1 inhibition and tumor immunity

WEE1抑制和肿瘤免疫

基本信息

批准号：
10440520
负责人：
Bin Zhang
金额：
$ 41.16万
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/10440520
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 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.

项目摘要肿瘤采用许多机制来促进免疫逃逸，包括免疫逃逸。肿瘤微环境中不同免疫抑制细胞的浸润，调节性T细胞（Treg）。然而，肿瘤细胞内调节肿瘤生长的特定信号引起肿瘤诱导免疫抑制的TGFAP的募集仍然存在，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调节剂，维持免疫抑制和促免疫作用致瘤微环境，并抑制WEE 1活性，包括通过临床相关的WEE 1抑制剂，可能是治疗上有益的，通过加强免疫介导的肿瘤清除率该提案旨在描述新的监管视角 WEE1介导的肿瘤细胞和宿主免疫细胞之间的串扰，大力推进领域。具体来说，这个项目正在寻找 WEE1介导的Treg调节机制和新的有效的组合策略。因此，我们的工作将确定WEE1的未被重视的作用抑制逆转肿瘤诱导的免疫抑制。