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

该奖项将培训牙医科学家凯尔维宁博士在免疫肿瘤学，并帮助他过渡到 一个独立的研究生涯，专注于开发新的策略，以重新编程骨髓的命运在头部 和颈部癌症。几种免疫疗法被批准用于头颈部鳞状细胞癌 （HNSCC），但尽管有这些进展，报告的反应率仅为13%， 在复发性/转移性HNSCC中使用纳武单抗的检查点阻断单药治疗。存在未满足的临床 需要确定实体瘤中免疫抵抗的机制。为了解决这个问题，我们将重点放在 机械信号在纤维化肿瘤中对髓样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。对于力学如何能够 直接影响肿瘤中免疫细胞的命运。这个应用程序将剖析力学的作用 肿瘤中的骨髓细胞，建立在显示应力松弛的强有力的初步数据上，或 细胞外基质的黏弹性在体外调节未成熟单核细胞。研制了一种人工电子对抗系统， 独立地将纤维状胶原基质调节至与实体瘤相似硬度， 粘性或更类似固体的弹性性质。粘性，坚硬的基质维持未成熟的单核细胞，而 弹性、刚性基质指导单核细胞分化为树突状细胞，并上调前 炎性细胞因子这些数据表明单核细胞命运是由机械的 在人类实体肿瘤中的调节。第一个目标将在达纳法伯癌症指导下进行 免疫肿瘤学家F。Stephen Hodi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 机械转导的单核细胞的转录程序，并确定这些分子是否 特征与口腔SCC患者样本中不利的临床结果相关。维宁医生 我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，以及与生物信息学合作。最后，在目标2的独立阶段， 博士Vining的实验室将在体外和体内确定单核细胞命运的靶向机械调节的效果。 vivo.人工ECM系统将识别控制单核细胞命运的靶标，然后将在一个实验室中进行测试。 口腔癌动物模型。总之，这些目标将共同决定单核细胞的调节 并将开发新的策略来靶向骨髓细胞用于治疗HNSCC。 此外，这些发现可能会启动新的研究领域，以了解机械提示如何 调节骨髓细胞的稳态、疾病和再生。

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.