Sustaining Tissue Resident Memory T cells

维持组织驻留记忆 T 细胞

• 批准号: 10389592
• 负责人: Yina Hsing Huang
• 金额: $ 53.75万
• 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/10389592
• 关键词: Address; 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; Recurrence; Reporting; Role; Sentinel; Signal Transduction; Site; Skin; Skin Tissue; Survivors; T memory cell; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; Transcript; Tumor Immunity; Tumor Tissue; Virus Diseases; Vitiligo; Work; anti-melanoma immunity; base; chemokine; chemokine receptor; draining lymph node; lymph nodes; melanoma; memory recall; memory retention; mouse model; novel; programs; residence; response; 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.

摘要 对癌症的持久免疫力是由记忆T细胞维持的。与循环存储子集相反，循环存储子集 进出血液的交通，组织驻留记忆(TRM)细胞被转录编程，以延长 在组织内的驻留和回忆功能。我们实验室之间的合作研究是第一批 确定TRM细胞在抗癌免疫中的需求。使用黑色素瘤相关性白癜风(MAV)小鼠 与免疫检查点抑制剂治疗的黑色素瘤患者发生白癜风非常相似的模型 谁受益于延长的无病生存，我们表明皮肤TRM细胞是必要的和充分的 针对真皮黑色素瘤的长期保护性免疫。然而，控制TRM细胞的机制 TRM细胞在肿瘤频繁转移部位的持久性和同一性及其在肿瘤免疫中的作用 目前仍不清楚。在这个应用中，我们研究了皮肤中TRM细胞维持的一种意想不到的机制 并揭示了一个新的至关重要的TRM细胞亚群，这些细胞持续存在于肿瘤引流的淋巴结中。 免疫荧光成像显示，感染MAV的小鼠以及患有白癜风的黑色素瘤患者的皮肤 TRM细胞形成的淋巴聚集体包含大量表达CD11c的髓系细胞。而当 先前的工作表明，CD11c+树突状细胞(DC)对于启动免疫反应是关键的，但却是必不可少的 为了重新激活TRM，我们发现CD11c表达细胞的耗尽会导致快速解聚和丢失 皮肤中的CD8TRM细胞。我们进一步证明CXCR6/CXCL16轴是TRM细胞持续存在所必需的，并且 皮肤中的肿瘤保护。这些发现确定了表达CXCL16的髓系细胞的关键要求 在协调组织中表达CXCR6的TRM的组织和保留方面，这将在 特定目的1.CXCR6/CXCL16轴和持续自身抗原在控制TRM细胞中的重要性 功能和可塑性将在特定的目标2中进行测试。最后，将在淋巴中探索并行机制 结节(LN)，我们的初步研究使我们发现了一种新的肿瘤特异性T细胞群体，即 对防止淋巴结黑色素瘤生长至关重要。LN TRM细胞的存在以前没有 在癌症的背景下被展示出来。APC和趋化因子在维持这种反应中的作用是 基本上是未知的，并将成为具体目标3的重点。因此，这项提议将考验总体目标 假设肿瘤特异性TRM细胞--包括皮肤和引流淋巴结中的--依赖于与 APC和趋化因子用于其正确的定位、维持和抗肿瘤功能。