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是由记忆 T 细胞维持的。与循环记忆子集相反， 组织驻留记忆 (TRM) 细胞在进出血液的过程中经过转录编程，可长时间保存 组织内的驻留和回忆功能。我们实验室之间的合作研究是最早的 确定 TRM 细胞对癌症免疫的要求。使用黑色素瘤相关白癜风 (MAV) 小鼠 模型非常模仿免疫检查点抑制剂治疗的黑色素瘤患者中出现的白癜风 我们证明皮肤 TRM 细胞对于受益于长期无病生存的人来说是必要且充分的 针对真皮中黑色素瘤的长期保护性免疫力。然而，控制 TRM 细胞的机制 持久性和同一性以及 TRM 细胞对频繁转移部位的肿瘤免疫的贡献 仍不清楚。在此应用中，我们研究了皮肤中 TRM 细胞维持的一种意想不到的机制 并揭示了一个新的极其重要的 TRM 细胞亚群，它们持续存在于肿瘤引流淋巴结中。 免疫荧光成像显示，在患有 MAV 的小鼠以及患有白癜风的黑色素瘤患者的皮肤中 TRM 细胞形成含有大量表达 CD11c 的骨髓细胞的淋巴聚集体。尽管 先前的工作表明 CD11c+ 树突状细胞 (DC) 对于启动免疫反应至关重要，但可有可无 为了重新激活 TRM，我们发现 CD11c 表达细胞的耗竭会导致快速解聚和损失 皮肤中的 CD8 TRM 细胞。我们进一步表明，CXCR6/CXCL16 轴是 TRM 细胞持久性所必需的，并且 皮肤肿瘤保护。这些发现确定了表达 CXCL16 的骨髓细胞的关键要求 协调组织中表达 CXCR6 的 TRM 的组织和保留，这将在 具体目标 1. CXCR6/CXCL16 轴和持续自身抗原在控制 TRM 细胞中的重要性 功能和可塑性将在具体目标2中进行测试。最后，将在淋巴中探索并行机制 节点（LN），我们的初步研究使我们发现了一个新的肿瘤特异性 T 细胞群， 对于防止淋巴结中黑色素瘤的生长至关重要。 LN TRM 细胞的存在以前从未出现过 已在癌症环境中得到证实。 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，并将成为具体目标 3 的重点。因此，该提案将测试总体目标 假设肿瘤特异性 TRM 细胞（在皮肤和引流淋巴结中）依赖于与 APC 和趋化因子的正确定位、维护和抗肿瘤功能。