Dissecting the tumor-intrinsic and -extrinsic roles of TBK1 in tumor immunity

解析 TBK1 在肿瘤免疫中的肿瘤内在和外在作用

• 批准号: 10716636
• 负责人: Russell William Jenkins
• 金额: $ 63.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10716636
• 关键词: Accounting; Adult; Biological Markers; Biological Models; Biology; CD8-Positive T-Lymphocytes; Cell Death; Cell physiology; Cells; Cessation of life; Clinical; Data; Databases; Development; Diagnosis; Experimental Models; Functional disorder; Genes; Genetic; Genetic Screening; Goals; Immune; Immune Evasion; Immunotherapy; In Vitro; Inflammatory; Inflammatory Response; Knockout Mice; Laboratories; Lymphoid Cell; Macrophage; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Nature; PD-1 blockade; PD-1/PD-L1; PDL1 pathway; Patients; Population; Production; Protein Kinase; Publishing; RIPK1 gene; Regulation; Resistance; Role; Signal Transduction; Skin Cancer; T-Lymphocyte; TANK-binding kinase 1; TNF gene; Testing; Therapeutic; Tumor Immunity; Tumor-infiltrating immune cells; United States; Woman; anti-tumor immune response; cancer cell; cancer immunotherapy; cell type; conditional knockout; cytokine; cytotoxicity; effective therapy; effector T cell; exhaust; exhaustion; immune checkpoint blockade; in vivo; insight; loss of function; melanoma; men; molecular targeted therapies; mouse model; neoplastic cell; novel; novel therapeutic intervention; pharmacodynamic biomarker; pharmacologic; progenitor; response; restraint; single-cell RNA sequencing; success; tool; treatment strategy; tumor; tumor microenvironment

Project Summary Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 pathway has induced dramatic and durable clinical responses in melanoma and other cancers. Despite the success of ICB, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. TANK-binding kinase 1 (TBK1) is a versatile innate immune protein kinase nominated as a candidate immune evasion gene in a number of pooled genetic screens. Using genetic and pharmacologic tools across multiple experimental model systems, we have confirmed a role for TANK-binding kinase 1 (TBK1) as an immune evasion gene. Targeting TBK1 enhances response to ICB by lowering the cytotoxicity threshold to effector cytokines (TNFa/IFNg) secreted by immune cells. Tumor cells lacking TBK1 are primed to undergo RIPK1-dependent cell death in response to TNFa/IFNg. Beyond its effect on cancer cells, targeting TBK1 in immune cells appears to augment this effect as TBK1 inhibition +/- PD-1 blockade not only promoted accumulation of effector/progenitor exhausted CD8 T cells and M1-like macrophages, but was sufficient to enhance production of inflammatory cytokines (e.g., IFNg, TNFa) from these cells. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy and raise important questions about the function of TBK1 in cancer cells versus immune cells in tumor immunity. In this proposal, we aim to confirm and extend these initial observations and resolve the cell type specific roles of TBK1 in tumor immunity. In Aim 1, we will determine the cancer cell-specific roles and regulation of TBK1 in resistance to cancer immunotherapy, by defining the downstream substrates of TBK1 in the setting of ICB resistance and defining upstream the mechanism(s) of TBK1 regulation promoting immune evasion. In Aim 2, we define the T cell-specific role of TBK1 in anti-tumor immunity by examining the effect of conditional deletion of TBK1 in CD8+ T cells. We will use CD8+ T cell specific TBK1 conditional knockout mouse models to define the effect of TBK1 deletion in T cells on the efficacy of ICB and profile of tumor-infiltrating immune cells, and CD8+ T cell effector function/dysfunction. In Aim 3, we will dissect the role of TBK1 in regulating intratumoral myeloid cells. Using myeloid-specific TBK1 conditional knockout mouse models, we will define the effect of myeloid-specific TBK1 deletion on the efficacy of ICB and the landscape of tumor infiltrating immune cells, as well as the effector function of macrophages and other myeloid cell populations.

项目摘要 靶向PD-1/PD-L1通路的免疫检查点阻断（ICB）已经诱导了显著和持久的临床应用。 在黑色素瘤和其他癌症中的反应。尽管ICB取得了成功，但有效的治疗策略， 缺乏克服癌症免疫疗法的抵抗力。TANK结合激酶1（TBK 1）是一种多功能的先天性 免疫蛋白激酶在许多合并的遗传筛选中被提名为候选免疫逃避基因。 通过在多个实验模型系统中使用遗传和药理学工具，我们已经证实了 TANK结合激酶1（TBK 1）作为免疫逃避基因。靶向TBK 1通过以下方式增强对ICB的反应： 降低对免疫细胞分泌的效应细胞因子（TNF α/IFNg）的细胞毒性阈值。肿瘤细胞 缺乏TBK 1的细胞被引发以响应于TNF α/IFNg而经历RIPK 1依赖性细胞死亡。超越其影响 在癌细胞上，靶向免疫细胞中的TBK 1似乎增强了这种作用，因为TBK 1抑制+/- PD-1 阻断不仅促进效应/祖细胞耗尽的CD 8 T细胞和M1样T细胞的积累， 巨噬细胞，但足以增强炎性细胞因子的产生（例如，IFNg、TNFa）从这些 细胞总之，我们的结果表明，靶向TBK 1是一种新颖有效的策略，可以克服 对癌症免疫疗法的抵抗，并提出了关于TBK 1在癌细胞中的功能的重要问题 与肿瘤免疫中的免疫细胞相比。在本提案中，我们旨在确认和扩展这些初步观察结果 解决TBK 1在肿瘤免疫中的细胞类型特异性作用。 在目标1中，我们将确定TBK 1在癌症抗性中的癌细胞特异性作用和调节 免疫治疗，通过定义TBK 1在ICB耐药背景下的下游底物， 上游TBK 1调节机制促进免疫逃避。 在目的2中，我们通过检测条件性的TBK 1对T细胞的作用，确定了TBK 1在抗肿瘤免疫中的特异性作用。 CD 8 + T细胞中TBK 1的缺失。我们将使用CD 8 + T细胞特异性TBK 1条件性敲除小鼠模型， 确定T细胞中TBK 1缺失对ICB功效和肿瘤浸润免疫细胞谱的影响， 和CD 8 + T细胞效应子功能/功能障碍。 在目标3中，我们将剖析TBK 1在调节肿瘤内髓样细胞中的作用。使用骨髓特异性TBK 1 条件性基因敲除小鼠模型，我们将确定骨髓特异性TBK 1缺失对疗效的影响 ICB和肿瘤浸润免疫细胞的景观，以及巨噬细胞的效应功能， 其他骨髓细胞群。