Targeting mechanical regulation of monocyte fate in head and neck cancer.

针对头颈癌中单核细胞命运的机械调节。

基本信息

批准号：
10377488
负责人：
Kyle Holmberg Vining
金额：
$ 13.5万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10377488
关键词：
Address Animal Model Archives Area Automobile Driving Award Behavior Bioinformatics Bone Marrow Bone Regeneration Cells Clinical Collagen Dana-Farber Cancer Institute Data Dendritic Cells Dental Dentists Disease Educational workshop Elasticity Encapsulated Enzymes Exclusion Exhibits Extracellular Matrix Fibrillar Collagen Fibrosis Gel Genetic Transcription Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Homeostasis Human I-kappa B Proteins Immature Monocyte Immune Immunologist Immunooncology Immunophenotyping Immunotherapy In Vitro Incidence Inflammation Inflammatory Investigation Knowledge Learning Liquid substance Malignant Neoplasms Mechanics Mentors Metastatic/Recurrent Molecular Molecular Profiling Myelogenous Myeloid Cells Myeloid-derived suppressor cells Natural regeneration Nivolumab Oncologist Oral Outcome Pathologic Patient Care Patients Periodontal Diseases Phase Play Population Property Pulpitis Regulation Relaxation Reporting Research Resistance Role STAT3 gene Sampling Scientist Solid Solid Neoplasm Squamous Cell Stress Stromal Cells System T-Lymphocyte Testing Tissues Training Treatment Efficacy Tumor Cell Invasion Tumor Immunity Tumor stage Tumor-infiltrating immune cells Unfavorable Clinical Outcome Up-Regulation Work advanced disease anti-PD-1 anti-PD-L1 base career crosslink curative treatments cytokine directed differentiation immune checkpoint blockade immune resistance improved in vivo inhibitor insight malignant mouth neoplasm mechanical properties mechanical signal medical schools monocyte multidisciplinary novel strategies patient prognosis programs response single-cell RNA sequencing transcription factor tumor tumor immunology tumor progression tumor-immune system interactions viscoelasticity

项目摘要

This award will train dentist-scientist Dr. Kyle Vining in immuno-oncology and help him transition to an independent research career focused on developing novel strategies to re-program myeloid fate in head and neck cancer. Several immunotherapies are approved for head and neck squamous cell carcinoma (HNSCC), but despite these advances, the reported response rate was only 13% in patients treated with checkpoint blockade monotherapy with nivolumab in recurrent/metastatic HNSCC. There is an unmet clinical need to identify mechanisms of immune resistance in solid tumors. To address this problem, we focus on the yet unknown role of mechanical cues on myeloid cells in fibrotic tumors. Solid tumors are surrounded by a rigid stroma of extracellular matrix (ECM). A significant gap of knowledge remains of how mechanics can directly impact the fate of immune cells in tumors. This application will dissect the role of mechanics on myeloid cells in tumors, building on strong preliminary data that showed the stress-relaxation, or viscoelasticity, of ECM regulates immature monocytes in vitro. An artificial ECM system was developed to independently tune fibrillar collagen matrix to stiffness similar to solid tumors, with either more fluid-like, viscous or more solid-like, elastic properties. Viscous, stiff matrix maintained immature monocytes, whereas elastic, stiff matrix directed differentiation of monocytes into dendritic cells and upregulated secretion of pro- inflammatory cytokines. These data suggest the hypothesis that monocyte fate is directed by mechanical regulation in human solid tumors. The first Aim will be conducted under mentoring at Dana-Farber Cancer Institute by immuno-oncologists Dr. F. Stephen Hodi and Dr. Ravindra Uppaluri, as well as cancer immunologist Dr. Kai Wucherpfennig. These supporting data and artificial ECM will be used to identify mechanically-transduced transcriptional programs of monocytes and determine whether these molecular signatures are associated with unfavorable clinical outcomes in patient samples of oral SCC. Dr. Vining will participate in Harvard Medical School workshops and courses to learn R-programming and bioinformatics analyses, as well as work with a collaborator in bioinformatics. Finally, in the independent phase in Aim 2, Dr. Vining's lab will determine the effects of targeting mechanical regulation of monocytes fate in vitro and in vivo. The artificial ECM system will identify targets to control monocyte fate, which then will be tested in an animal model of oral cancer. In conclusion, these Aims together will determine the regulation of monocytes by mechanical cues and will develop new strategies to target myeloid cells for the treatment of HNSCC. Further, these findings will potentially launch new areas of investigation into how mechanical cues regulate myeloid cells in homeostasis, disease, and regeneration.

该奖项将培训牙医科学家凯尔·维辛（Kyle Vining）博士在免疫肿瘤学领域，并帮助他过渡到独立的研究职业专注于制定新型策略，以重新编程髓样命运和颈部癌。几种免疫疗法被批准用于头颈鳞状细胞癌（HNSCC），但是尽管有这些进展，接受治疗的患者的缓解率仅为13％在复发/转移性HNSCC中使用Nivolumab的检查点阻断单一疗法。有一个未满足的临床需要鉴定实体瘤中免疫耐药性的机制。为了解决这个问题，我们专注于机械线索在纤维化肿瘤中的机械线索对髓样细胞的作用未知。实体瘤被包围细胞外基质（ECM）的刚性基质。知识的很大差距仍然存在力学如何直接影响肿瘤中免疫细胞的命运。该应用将剖析力学在肿瘤中的髓样细胞，建立在强大的初步数据上，该数据显示应力 - 释放或 ECM的粘弹性调节体外未成熟的单核细胞。开发了人工ECM系统独立调整原纤维胶原蛋白基质的刚度类似于实体瘤，两种流体样粘性或更固体的弹性特性。粘性，硬基质保持不成熟的单核细胞，而弹性，僵硬的基质将单核细胞分化为树突状细胞，并上调炎症细胞因子。这些数据表明单核细胞命运是由机械指导的假设人类实体瘤的调节。第一个目标将在Dana-Farber Cancer的指导下进行 Institute由免疫肿瘤学家F. Stephen Hodi博士和Ravindra Uppaluri博士以及癌症免疫学家Kai Wucherpfennig博士。这些支持数据和人工ECM将用于识别单核细胞的机械传输转录程序，并确定这些分子是否是否签名与口服SCC的患者样本中的不利临床结局有关。 Vining博士将参加哈佛医学院的研讨会和课程，以学习R编程和生物信息学分析以及与生物信息学合作者合作。最后，在AIM 2的独立阶段， Vining博士的实验室将确定单核细胞的机械调节在体外和IN的影响体内。人工ECM系统将识别控制单核细胞命运的目标，然后将其测试口腔癌的动物模型。总之，这些目标将共同确定单核细胞的调节通过机械提示，将制定新的策略来靶向髓样细胞以治疗HNSCC。此外，这些发现将有可能启动有关机械提示的新调查领域调节体内平衡，疾病和再生中的髓样细胞。