Tissue Resident memory T cell responses to cancer

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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.