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: 10363630
• 负责人: Jose Alejandro Guevara-Patino
• 金额: $ 36.92万
• 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/10363630
• 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; 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CD 8 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，这是记忆的基本原则。 组建尚待确定。我们建议研究和操纵CD 8 T细胞 NKG 2D/DAP 10通过核糖体蛋白S6（rpS 6）途径产生持久的保护性 抗肿瘤免疫这项研究的科学前提来自于我们的工作， NKG 2D信号传导为CD 8 T细胞提供促记忆信号。我们假设NKG 2D， 通过微调的DAP 10 PI 3 K/Grb 2信号（因为NKG 2D不能自己发送信号，而是使用 DAP 10 PI 3 K/Grb 2作为信号转导衔接子），激活rpS 6，导致功能性的 CD 8记忆T细胞该提案将定义rpS 6所需的底层参与者 NKG 2D/DAP 10下游的磷酸化及其在发展中的意义 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测试，目的是为临床试验做准备。 SA 1：确定NKG 2D-DAP 10诱导的 rpS 6的磷酸化 SA 2.为了确定NKG 2D/DAP 10 PI 3 K/GRB 2在细胞生长发育中的作用， 黑色素瘤的传统记忆反应和皮肤TRM细胞。 SA 3.为了增强操纵 CD 8 T细胞中的DAP 10/rpS 6通路