Elucidate and Modulate TGF-b Signaling in NK Cells for Glioma Treatment

描述(申请人提供)：转化生长因子-β(转化生长因子-β)对多种免疫细胞有深刻的免疫抑制作用。自然杀伤(NK)细胞是构成天然免疫系统的重要组成部分的大颗粒淋巴细胞。NK细胞产生丰富的干扰素-γ(IFN-？)为了增强肿瘤细胞的识别和破坏，并清除病毒感染，包括胶质母细胞瘤(GBM)治疗中的单纯疱疹病毒溶瘤病毒(OVS)。由于其复杂性，转化生长因子-？信号还没有完全被描述出来。是否有转化生长因子-β？本身还是转化生长因子？可以通过信号调节来调控NK细胞的功能，从而更好地控制肿瘤的进展，提高卵巢癌的治疗效果。我们假设转化生长因子-？可以进一步阐明和调节NK细胞中的信号转导，以更好地了解癌症的进展和加强癌症的治疗。我们的目标是研究转化生长因子-1的分子基础。通过鉴定直接参与这一过程的元件来抑制NK的抗肿瘤活性，并研究 前转化生长因子-β可增加信号转导，提高NK抗肿瘤活性，但降低NK活性。在卵巢治疗的背景下进行治疗，即NK细胞限制卵巢的扩张和治疗效果。我们提出的研究有很大的潜力推进GBM的治疗和/或GBM的预防，并使我们对肿瘤和病毒的识别和破坏有更多的了解。我们将通过三个目标来验证我们的假设：1)确定转化生长因子-β对NK细胞功能转录抑制的分子基础；2)我们能否干扰转化生长因子-β？信号增强免疫反应，进而控制体内GBM的进展？3)增强转化生长因子？NK细胞信号转导增强卵巢癌治疗效果的研究。

DESCRIPTION (provided by applicant): Transforming Growth Factor-Beta (TGF-?) has profound immunosuppressive effects on a variety of immune cells. Natural killer (NK) cells are large granular lymphocytes that constitute a vital component of the innate immune system. NK cells produce abundant interferon gamma (IFN-?) to enhance tumor cell recognition and destruction, and to clear viral infection, including herpes simplex oncolytic viruses (OVs) in glioblastoma (GBM) treatment. Due to its complexity, TGF-? signaling has not been fully characterized. It also remains to be determined whether TGF-? itself or TGF-? signaling can be modulated to control NK cell functions in order to better control tumor progression and to enhance OV therapeutic efficacy in GBM. We hypothesize that TGF-? signaling can be further elucidated and modulated in NK cells to better understand cancer progression and enhance cancer treatment. Our goal is to investigate the molecular basis of how TGF-? suppresses NK anti-tumor activity by identifying the elements directly involved in this process, and to study the potential to increase the signaling to improve NK anti-tumor activity, but to decrease NK activity by pre-TGF-? treatment in the context of OV therapy, where NK cells limit OV expansion and therapeutic efficacy. Our proposed studies have a great potential to advance GBM treatment and/or GBM prevention and make us understand more about tumor and virus recognition and destruction. We will test our hypothesis through three Aims: 1) To determine the molecular basis of transcriptional repression of NK cell function by TGF-?; 2) Can we disrupt TGF-? signaling to increase immune responses, and, in turn, to control GBM progression in vivo? 3) To augment TGF-? signaling in NK cells to enhance OV therapy efficacy in GBM.