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方面的知识，并帮助他过渡到 独立的研究生涯专注于开发新的策略来重新编程头部的髓系命运 和颈癌。几种免疫疗法已被批准用于头颈部鳞状细胞癌 (HNSCC)，但尽管有这些进展，报告的应答率只有13%，在接受 检查点阻断单抗治疗复发/转移性HNSCC有一个未满足的临床 需要确定实体肿瘤的免疫耐药机制。为了解决这个问题，我们重点关注 然而，机械信号在纤维性肿瘤中对髓系细胞的作用尚不清楚。实体瘤被 细胞外基质(ECM)的硬质基质。关于力学是如何实现的，仍然存在一个很大的知识空白 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在 肿瘤中的髓样细胞，建立在显示应力松弛的强大初步数据的基础上，或 细胞外基质的粘弹性在体外调节未成熟单核细胞。开发了一种人工ECM系统，以 独立调节纤维状胶原基质，使其硬度类似于实体瘤，具有更多的液体样， 粘性的或更像固体的弹性性质。粘稠、僵硬的基质维持未成熟的单核细胞，而 弹性、僵硬的基质定向单核细胞分化为树突状细胞，上调PRO-2的分泌 炎性细胞因子。这些数据表明，单核细胞的命运由机械性因素决定 对人体实体瘤的调控。第一个目标将在达纳-法伯癌症中心的指导下进行 由免疫肿瘤学家F.Stephen Hodi博士和Ravindra Uppaluri博士建立的研究所，以及癌症 免疫学家凯·乌切普芬尼格博士。这些支持数据和人工ECM将用于确定 机械转导的单核细胞转录程序，并确定这些分子 口腔鳞状细胞癌患者样本中的信号与不良的临床结果相关。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，以及与生物信息学的合作者合作。最后，在目标2的独立阶段， 维宁博士的实验室将在体外和体外确定靶向机械调节单核细胞命运的效果 活着。人工ECM系统将识别控制单核细胞命运的目标，然后将在 口腔癌动物模型的建立。总之，这些目标共同决定了单核细胞的调节。 通过机械提示，并将开发新的策略，靶向髓系细胞治疗HNSCC。 此外，这些发现可能会开启新的研究领域，研究机械线索是如何 调节髓系细胞的动态平衡、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.