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

T 细胞中 NKG2D 和核糖体蛋白 S6 信号传导的抗肿瘤免疫和组织驻留记忆细胞发育研究

• 批准号: 10448715
• 负责人: Jose Alejandro Guevara-Patino
• 金额: $ 34.48万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-14 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448715
• 关键词: Accreditation; Agonist; Autologous; Automobile Driving; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Structures; Certification; Clinical Trials; Data; Defect; Development; Effector Cell; Engineering; FRAP1 gene; Failure; Flow Cytometry; Gene Expression; Generations; Genetic; Goals; Human; Immune; Immunologic Memory; Immunotherapy; Impairment; Individual; Intention; Interleukin-15; Intervention; Maintenance; Malignant Neoplasms; Memory; Microscopic; Modeling; Molecular; Monoclonal Antibodies; Mus; Pathway interactions; Pharmacology; Phase; Phosphorylation; Play; Process; Production; Protein Biosynthesis; Repression; Ribosomal Protein S6; Role; Signal Transduction; Skin; Stat5 protein; T cell response; T memory cell; T-Lymphocyte; TSC1 gene; Testing; Therapeutic; Thymus Gland; Time; Transgenic Organisms; Tumor Immunity; Tumor Tissue; Western Blotting; Work; base; cell growth regulation; clinically relevant; experimental study; growth factor receptor-bound protein 2; inhibitor/antagonist; melanoma; mouse model; patient derived xenograft model; precursor cell; receptor; reconstitution; response; transcription factor; tumor; tumor growth; tumor immunology

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

在肿瘤免疫学领域，抗肿瘤CD8 T细胞的生成和维持 记忆反应被认为对于宿主的长期生存至关重要，这是记忆的基本原理 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 这项研究的科学前提源自我们的工作证明： NKG2D 信号为 CD8 T 细胞提供促记忆信号。 通过精细调整的 DAP10PI3K/Grb2 信号传输（因为 NKG2D 无法自行发出信号，而是使用 DAP10PI3K/Grb2 作为信号适配器），激活 rpS6，从而导致功能发育 该提案将定义 rpS6 所需的潜在参与者。 NKG2D/DAP10 下游的磷酸化及其对发育的影响 针对肿瘤（包括 TRM 细胞）的免疫记忆在这里我们将进行概念验证。 利用人类和小鼠肿瘤进行测试，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 在开发中的作用 传统记忆反应和皮肤 TRM 细胞对抗黑色素瘤。 SA3. 评估操纵的治疗潜力 CD8 T 细胞中的 DAP10/rpS6 通路