Tissue Resident memory T cell responses to cancer

摘要 驻留记忆（Trm）细胞是一种长寿命的组织定位的CD 8 T细胞区室，其充当关键的免疫调节因子。 针对癌症进展和转移免疫屏障。我们对R 01的前一个周期的研究表明， 黑色素瘤特异性Trm群分布在皮肤和肿瘤引流淋巴结中， （TDLN），其中它们在小鼠中提供针对原发性和转移性黑素瘤的保护。在人类中，我们发现 具有相似特征的Trm群体在黑色素瘤幸存者的皮肤中持续多年。 然而，外地对指导建立、运作和 Trm群体在不同组织位置的相互转化。这次复兴的首要目标是 应用程序旨在定义程控要求、运输要求和潜在临床受益， 定位于肿瘤引流淋巴结的肿瘤特异性Trm细胞。根据我们的初步数据， 淋巴结（LN）中的群体独特地需要1型干扰素（IFN）信号来产生，特异性 目的1将定义的机制和时间的1型干扰素的生产是至关重要的LN Trm的形成。我们 将定义1型IFN感知的关键窗口，以及在过程中控制这种感知的细胞相互作用。 Trm单元编程和维护。我们还将确定cGAS/STING途径在 向TDLN中的Trm细胞提供IFN信号。因此，我们期望揭示1型IFN作为促进细胞增殖的关键细胞因子， LN限制的Trm生成。第二，基于我们的发现，Trm细胞从皮肤运输到引流LN， 对黑色素瘤的原发反应和回忆反应，具体目标2将定义这些组织之间的动力学- 封闭车厢通过限制T细胞归巢到外周组织，我们将定义组织通路在 支持LN中的Trm播种。我们还将确定皮肤与肿瘤出口对Trm的相对贡献 在LNS中生成。然后，我们将定义皮肤和LN之间的Trm细胞命运和分化轨迹，以测试 皮肤是对抗黑色素瘤的功能性T细胞反应的储存库的挑衅性假设。 最后，具体目标3将定义LN Trm人群在患者中的功能和预后意义。 黑色素瘤和非小细胞肺癌（NSCLC）。这些研究将检验区域LN Trm 群体与对淋巴结转移的抗性相关。我们的研究将确定功能，茎， 与转移保护相关的人LN Trm群体的可塑性。通过定义机制 潜在的组织特异性Trm生成，这项工作将支持我们的总体目标， 在癌症生长和转移的整个组织中的反应。

ABSTRACT Resident memory (Trm) cells are a long-lived tissue localized CD8 T cell compartment that serves as a critical immune barrier against cancer progression and metastasis. Our work on the prior cycle of this R01 has shown that melanoma-specific Trm populations become distributed across skin and tumor-draining lymph nodes (TDLNs) where they provide protection against primary and metastatic melanoma in mice. In humans, we found that Trm populations with similar characteristics are sustained for years in the skin of melanoma survivors. However, the field lacks a clear understanding of mechanisms governing the establishment, function, and interconversion of Trm populations across different tissue locations. The overarching goal of this renewal application is to define the programming requirements, trafficking requirements, and potential clinical benefit of tumor-specific Trm cells that localize to tumor-draining lymph nodes. Based on our preliminary data that Trm populations in lymph nodes (LNs) uniquely require type-1 interferon (IFN) signals for their generation, Specific Aim 1 will define the mechanisms and timing of type-1 IFN production that are crucial for LN Trm formation. We will define the critical window of type-1 IFN sensing, and the cellular interactions that govern this sensing during Trm cell programming and maintenance. We will also determine the importance of the cGAS/STING pathway in providing IFN signals to Trm cells in TDLNs. Thus, we expect to reveal type-1 IFN as a key cytokine for promoting LN-restricted Trm generation. Second, based on our finding that Trm cells traffic from skin to draining LNs during primary and recall responses to melanoma, Specific Aim 2 will define the dynamics between these tissue- restricted compartments. By limiting T cell homing to peripheral tissue we will define a role for tissue access in supporting Trm seeding in LNs. We will also determine the relative contribution of skin vs. tumor egress to Trm generation in LNs. Then we will define Trm cell fate and differentiation trajectory between skin and LNs to test the provocative hypothesis that skin serves as a reservoir for functional T cell responses against melanoma. Finally, Specific Aim 3 will define the function and prognostic significance of LN Trm populations in patients with melanoma and non-small cell lung cancer (NSCLC). These studies will test the hypothesis that regional LN Trm populations correlate with resistance to metastasis to LNs. Our studies will define the function, stemness, and plasticity of human LN Trm populations that associate with protection from metastasis. By defining mechanisms underlying tissue-specific Trm generation, this work will support our overarching goal of generating Trm responses throughout tissues where cancers grow and metastasize.