Sustaining Tissue Resident Memory T cells

维持组织驻留记忆 T 细胞

• 批准号: 10544791
• 负责人: Yina Hsing Huang
• 金额: $ 52.68万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544791
• 关键词: Affect; Antigen-Presenting Cells; Antigens; Antitumor Response; Autoantigens; Autoimmunity; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCR6 gene; Cancer Remission; Cell Maintenance; Cell physiology; Cells; Data; Dendritic Cells; Dependence; Dermis; Disease-Free Survival; Excision; Future; Generations; Genetic Transcription; Growth; Hair follicle structure; ITGAX gene; Image; Immune checkpoint inhibitor; Immune response; Immunity; Immunologic Memory; Immunotherapy; Infection; Inflammation; Invaded; Knock-out; Laboratories; Location; Longevity; Lymph Node Subcapsular Sinus; Lymph Node Tissue; Lymphoid; Maintenance; Malignant Neoplasms; Memory; Modeling; Molecular; Mus; Myeloid Cells; Neoplasm Metastasis; Operative Surgical Procedures; Patients; Population; Positioning Attribute; Recurrent tumor; Reporting; Role; Sentinel; Signal Transduction; Site; Skin; Skin Tissue; Survivors; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Transcript; Tumor Cell Invasion; Tumor Immunity; Tumor Tissue; Virus Diseases; Vitiligo; Work; anti-melanoma immunity; chemokine; draining lymph node; lymph nodes; melanoma; memory recall; memory retention; mouse model; novel; receptor; residence; response; tissue resident memory T cell; tumor; tumor growth

ABSTRACT Durable immunity to cancer is sustained by memory T cells. In contrast to circulating memory subsets, which traffic in and out of the blood, tissue-resident memory (TRM) cells are transcriptionally programed for prolonged residence and recall function within tissue. Collaborative studies between our laboratories were among the first to identify a requirement for TRM cells in immunity to cancer. Using a melanoma-associated vitiligo (MAV) mouse model that closely mimics the vitiligo that develops in immune checkpoint inhibitor-treated melanoma patients who benefit from prolonged disease-free survival, we showed that skin TRM cells are necessary and sufficient for long term protective immunity against melanoma in the dermis. However, mechanisms for controlling TRM cell persistence and identity as well as the contribution of TRM cells to tumor immunity at sites of frequent metastasis remain unclear. In this application, we examine an unexpected mechanism for TRM cell maintenance in the skin and reveal a new subset of vitally important TRM cells that persist in tumor-draining lymph nodes. In the skin of mice with MAV, as well as melanoma patients with vitiligo, immunofluorescent imaging revealed that TRM cells form lymphoid aggregates containing large populations of CD11c-expressing myeloid cells. While prior work indicates that CD11c+ dendritic cells (DCs) are critical for initiating immune responses but dispensable for reactivating TRM we find that depletion of CD11c-expressing cells results in rapid disaggregation and loss of CD8 TRM cells in the skin. We further show that the CXCR6/CXCL16 axis is required for TRM cell persistence and tumor protection in the skin. These findings identify a critical requirement for CXCL16-expressing myeloid cells in coordinating the organization and retention of CXCR6-expressing TRM in the tissue, which will be examined in Specific Aim 1. The importance of the CXCR6/CXCL16 axis and persisting self antigen in controlling TRM cell function and plasticity will be tested in Specific Aim 2. Finally, parallel mechanisms will be explored in lymph nodes (LNs) where our preliminary studies led us to discover a novel population of tumor-specific T cells that is crucial for protection against melanoma growth in lymph nodes. The presence of LN TRM cells has not previously been shown in the setting of cancer. A role for APCs and chemokines in maintaining such responses is essentially unknown, and will be the focus of Specific Aim 3. This proposal will thus test the overarching hypothesis that tumor-specific TRM cells— both in skin and draining lymph nodes—rely on key interactions with APCs and chemokines for their proper positioning, maintenance, and anti-tumor function.

抽象的 对癌症的持久免疫力由记忆T细胞维持。与循环记忆子集相反， 输入和流入血液，居住的记忆（TRM）细胞经过转录编程以延长 居住和召回功能在组织中。我们实验室之间的协作研究是第一个 确定对癌症免疫的TRM细胞的要求。使用黑色素瘤相关的白癜风（MAV）小鼠 密切模仿在免疫检查点抑制剂治疗的黑色素瘤患者中发展的白癜风的模型 谁能从长时间的无病生存中受益，我们表明皮肤TRM细胞是必需的，足以满足 长期保护的免疫对真皮中的黑色素瘤。但是，控制TRM单元的机制 持久性和身份以及TRM细胞对经常转移部位的肿瘤免疫的贡献 保持不清楚。在此应用中，我们检查了皮肤中TRM细胞维持的意外机制 并揭示了一个新的重要重要TRM细胞子集，这些细胞持续存在于肿瘤淋巴结中。 在患有MAV的小鼠的皮肤中，以及白癜风的黑色素瘤患者，揭示了免疫荧光成像 TRM细胞形成淋巴聚集体包含大量表达CD11C的髓样细胞的群体。尽管 先前的工作表明CD11C+树突状细胞（DC）对于启动免疫调发至关重要，但可分配 为了重新激活TRM 皮肤中的CD8 TRM细胞。我们进一步表明，TRM单元格的持久性和 皮肤中的肿瘤保护。这些发现确定了表达CXCL16的髓样细胞的关键要求 在协调中，组织中表达CXCR6的TRM的组织和保留，将在 特定目标1。cxcr6/cxcl16轴的重要性和持续的自抗原控制TRM单元格 功能和可塑性将在特定的目标2中进行测试。最后，将在淋巴中探索平行机制 我们的初步研究导致我们发现了新的肿瘤特异性T细胞种群的节点（LNS） 对于防止淋巴结中黑色素瘤生长的保护至关重要。 LN TRM细胞的存在以前没有 在癌症的情况下显示。 APC和趋化因子在维持此类反应中的作用是 本质上是未知的，并且将成为特定目标3的重点。因此，该提案将测试总体 假设肿瘤特异性的TRM细胞（皮肤中的淋巴结和排水淋巴结）很依赖与关键相互作用 APC和趋化因子适当定位，维护和抗肿瘤功能。