Sustaining Tissue Resident Memory T cells

摘要 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， 在进出血液的交通中，组织驻留记忆（TRM）细胞被转录编程以延长 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 以确定TRM细胞在癌症免疫中的需求。使用黑色素瘤相关白癜风（MAV）小鼠 一种密切模仿免疫检查点通道治疗的黑色素瘤患者中发生的白癜风的模型 我们发现，皮肤TRM细胞是必要的，也是足够的， 长期保护免疫力，防止皮肤黑色素瘤。然而，控制TRM细胞的机制 持续性和同一性以及TRM细胞在频繁转移部位对肿瘤免疫的贡献 仍然不清楚。在这个应用程序中，我们研究了一个意想不到的机制，TRM细胞在皮肤中的维护 并揭示了一个新的至关重要的TRM细胞亚群，它们持续存在于肿瘤引流淋巴结中。 在MAV小鼠皮肤以及白癜风黑色素瘤患者的皮肤中，免疫荧光成像显示， TRM细胞形成淋巴聚集体，其中含有大量表达CD 11 c的骨髓细胞。而 先前的研究表明，CD 11 c+树突状细胞（DC）对于启动免疫应答至关重要，但它可能是一种免疫应答。 为了重新激活TRM，我们发现CD 11 c表达细胞的耗竭导致快速解聚和TRM的丧失。 皮肤中的CD 8 TRM细胞。我们进一步表明，CXCR 6/CXCL 16轴是TRM细胞持久性所必需的， 皮肤中的肿瘤保护。这些发现确定了表达CXCL 16的髓样细胞的关键要求 在协调组织中表达CXCR 6的TRM的组织和保留方面，这将在 具体目标1。CXCR 6/CXCL 16轴和持续性自身抗原在TRM细胞调控中的作用 功能和可塑性将在具体目标2中进行测试。最后，将探讨淋巴中的平行机制 淋巴结（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， 对于防止淋巴结中黑色素瘤的生长至关重要。LN TRM细胞的存在以前没有 在癌症的情况下被证明。APC和趋化因子在维持这种应答中的作用是 基本上是未知的，将是具体目标3的重点。因此，这一提议将考验 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。

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.