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。

• 批准号: 10686261
• 负责人: Kyle Holmberg Vining
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686261
• 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; Unfavorable Clinical Outcome; Up-Regulation; Viscosity; Work; advanced disease; anti-PD-1; anti-PD-L1; career; crosslink; curative treatments; cytokine; directed differentiation; immune cell infiltrate; immune checkpoint blockade; immune resistance; improved; in vivo; inhibitor; insight; malignant mouth neoplasm; mechanical drive; 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

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·维宁 (Kyle Vining) 博士进行免疫肿瘤学方面的培训，并帮助他过渡到 独立研究生涯专注于开发重新编程头部骨髓命运的新策略 和颈部癌症。几种免疫疗法被批准用于治疗头颈鳞状细胞癌 (HNSCC)，但尽管取得了这些进展，据报道，接受治疗的患者的缓解率仅为 13% 纳武单抗检查点阻断单药治疗复发/转移性 HNSCC。临床上还有一个未满足的问题 需要确定实体瘤的免疫抵抗机制。为了解决这个问题，我们重点关注 机械信号对纤维化肿瘤中骨髓细胞的作用尚不清楚。实体瘤周围有 细胞外基质 (ECM) 的刚性基质。关于力学如何能够 直接影响肿瘤中免疫细胞的命运。该应用程序将剖析力学的作用 肿瘤中的骨髓细胞，建立在显示压力松弛的强有力的初步数据的基础上，或者 ECM 的粘弹性在体外调节未成熟的单核细胞。开发了人工 ECM 系统 独立地将纤维状胶原基质调节至类似于实体瘤的硬度，具有更像流体的、 粘性或更接近固体的弹性特性。粘稠、僵硬的基质维持未成熟的单核细胞，而 弹性、刚性基质定向单核细胞分化为树突状细胞并上调促细胞因子的分泌 炎症细胞因子。这些数据表明单核细胞命运是由机械决定的假设 人类实体瘤的调控。第一个目标将在丹娜—法伯癌症研究所的指导下进行 由免疫肿瘤学家 F. Stephen Hodi 博士和 Ravindra Uppaluri 博士以及癌症研究所 免疫学家 Kai Wucherpfennig 博士。这些支持数据和人工 ECM 将用于识别 单核细胞的机械转导转录程序并确定这些分子是否 特征与口腔鳞状细胞癌患者样本的不良临床结果相关。维宁博士 将参加哈佛医学院的研讨会和课程，学习 R 编程和生物信息学 分析，以及与生物信息学领域的合作者合作。最后，在目标2的独立阶段， Vining 博士的实验室将确定体外和体内单核细胞命运的靶向机械调节的效果 体内。人工 ECM 系统将识别控制单核细胞命运的目标，然后在 口腔癌动物模型。总之，这些目标共同决定了单核细胞的调节 通过机械线索，并将开发新的策略来靶向骨髓细胞来治疗 HNSCC。 此外，这些发现可能会启动新的研究领域，研究机械线索如何 调节骨髓细胞的稳态、疾病和再生。