Study of Anti-Tumor Immunity and Tissue Resident Memory Cell Development by NKG2D and Ribosomal Protein S6 Signaling in T cells

在肿瘤免疫学领域，抗肿瘤CD8 T细胞的产生和维持 记忆反应被认为对宿主的长期生存至关重要，这是记忆的基本原理 编队还有待建立。我们建议研究和操纵CD8 T细胞 NKG2D/DAP10核糖体蛋白S6(RpS6)途径作为产生持久和保护性的手段 抗肿瘤免疫。这项研究的科学前提源于我们的工作，证明了 NKG2D信号为CD8T细胞提供促进记忆的信号。我们假设NKG2D， 通过微调的DAP10PI3K/Grb2信令(因为NKG2D本身无法发出信号，而是使用 DAP10PI3K/Grb2作为信号适配器)，激活rpS6，导致功能的发展 有能力的CD8记忆T细胞。该提案将定义rps6所需的基础角色。 NKG2D/DAP10下游的磷酸化及其在肿瘤发生发展中的意义 针对肿瘤的免疫记忆，包括TRM细胞。在这里，我们将进行概念验证 利用人类和小鼠肿瘤进行的测试，目的是为临床试验做准备。 SA1：确定NKG2D-DAP10诱导的分子贡献者 RpS6的磷酸化 SA2.确定NKG2D/DAP10PI3K/Grb2在肿瘤发生发展中的作用 传统记忆反应和皮肤TRM细胞抗黑色素瘤。 SA3.为了评估手法治疗的潜力 CD8 T细胞中的DAP10/rpS6通路

In the field of tumor immunology, while the generation and maintenance of anti-tumor CD8 T cell memory responses are considered crucial for the long-term host survival, the basic tenets of memory formation remain to be established. We propose to study and manipulate the CD8 T cell NKG2D/DAP10  ribosomal protein S6 (rpS6) pathway as a means to generate durable and protective anti-tumor immunity. The scientific premise of this study is derived from our work demonstrating that NKG2D signaling provides CD8 T cells with pro-memory signals. We hypothesize that NKG2D, through finely tuned DAP10PI3K/Grb2 signaling (as NKG2D cannot signal by itself, instead uses DAP10PI3K/Grb2 as signaling adaptor), activates rpS6 resulting in the development of functionally capable CD8 memory T cells. This proposal will define the underlying players required for rpS6 phosphorylation downstream of NKG2D/DAP10 and its implications in the development of immunological memory against tumors including TRM cells. Here we will conduct proof-of-concept tests utilizing human and mouse tumors, with the intention of preparing for a clinical trial. SA1: TO DETERMINE THE MOLECULAR CONTRIBUTORS OF NKG2D-DAP10 INDUCED PHOSPHORYLATION OF rpS6 SA2. TO DETERMINE THE ROLE OF NKG2D/DAP10PI3K/GRB2 IN THE DEVELOPMENT OF TRADITIONAL MEMORY RESPONSES AND SKIN TRM CELLS AGAINST MELANOMA. SA3. TO EVALUATE THE THERAPEUTIC POTENTIAL OF MANIPULATING THE DAP10/rpS6 PATHWAY IN CD8 T CELLS