Tissue Resident memory T cell responses to cancer

摘要 驻留记忆(Trm)细胞是一种长寿的组织定位的CD8 T细胞隔间，是关键的 防止癌症进展和转移的免疫屏障。我们对R01的上一个周期的工作表明 黑色素瘤特异性Trm群体分布在皮肤和肿瘤引流淋巴结中 (TDLN)，在那里它们提供对小鼠原发和转移性黑色素瘤的保护。在人类身上，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，该领域缺乏对管理建立、职能和 Trm种群在不同组织位置之间的相互转换。这次更新的首要目标是 应用是定义规划要求、贩运要求和潜在的临床益处 肿瘤特异性Trm细胞，定位于肿瘤引流淋巴结。根据我们的初步数据，Trm 淋巴结(LN)中的人群在其生成过程中独特地需要类型1干扰素(IFN)信号， 目标1将确定1型干扰素产生的机制和时机，这对LN Trm的形成至关重要。我们 将定义1型干扰素感应的关键窗口，以及控制这种感应的细胞相互作用 TRM单元编程和维护。我们还将确定cGAS/STING途径在 向TDLN中的Trm细胞提供干扰素信号。因此，我们希望揭示1型干扰素是促进 LN-受限的Trm生成。第二，基于我们的发现，Trm细胞在 对黑色素瘤的原发和回忆反应，特定的目标2将定义这些组织之间的动态- 限制舱。通过将T细胞归巢限制到外周组织，我们将定义组织访问在 支持在LNS中进行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。然后我们将确定Trm细胞在皮肤和LN之间的命运和分化轨迹以进行测试 这一具有挑衅性的假设认为，皮肤是对抗黑色素瘤的功能性T细胞反应的储备库。 最后，特定目标3将确定LN Trm人群在慢性粒细胞白血病患者中的功能和预后意义。 黑素瘤和非小细胞肺癌(NSCLC)。这些研究将检验区域LN Trm 人群与对淋巴结转移的抵抗有关。我们的研究将定义功能、茎和 与肿瘤转移保护相关的人类LN Trm群体的可塑性。通过定义机制 在组织特异性Trm生成的基础上，这项工作将支持我们生成Trm的总体目标 在癌症生长和转移的组织中产生反应。

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.