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 (TGF-?)对多种免疫细胞具有深远的免疫抑制作用。自然杀伤（NK）细胞是大颗粒淋巴细胞，构成先天免疫系统的重要组成部分。在胶质母细胞瘤（GBM）治疗中，NK细胞产生丰富的干扰素γ (IFN- γ)增强肿瘤细胞的识别和破坏，清除病毒感染，包括单纯疱疹溶瘤病毒（OVs）。由于其复杂性，TGF-？信号还没有被完全描述。TGF-？本身还是TGF-？通过调节信号通路控制NK细胞功能，从而更好地控制肿瘤进展，提高OV治疗GBM的疗效。我们假设TGF-？信号可以进一步阐明和调节NK细胞，以更好地了解癌症进展和加强癌症治疗。我们的目标是研究TGF-？通过鉴定直接参与这一过程的元素，来抑制NK抗肿瘤活性，并研究其作用机制

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.