Investigating T cell Circuits in the Lymphatic System During Melanoma Progression

About This Grant

PROJECT SUMMARY Tumor draining LNs (tdLN), are harbingers of aggressive disease, where the presence of metastases signals risk for recurrence and poor survival in melanoma patients. The tdLN basin, however, is also antigen-rich and may promote immune reinvigoration on immunotherapy. Indeed, recent neoadjuvant trials demonstrate increased efficacy when immune checkpoint blockade (ICB) is delivered prior to surgical resection, which may depend in part on the tdLN basin. Given that large-scale clinical trials failed to demonstrate the benefit of prophylactic, complete LN dissection in high-risk, LN-positive melanoma patients, there is an opportunity to consider the therapeutic potential of tdLNs as key hubs for continued tumor immune surveillance. Future progress, however, depends upon a mechanistic understanding for how anti-tumor immune surveillance in tdLNs is maintained and the impact of standard of care clinical therapy. Recent studies, both preclinical and clinical, have identified a subset of stem-like memory (TSL) cells CD8+ T cells that are produced as a function of suboptimal antigen presentation and are enriched in tdLNs. These TSL are reinvigorated upon ICB and required for response to therapy. Despite the fact that TSL are required for response to immunotherapy in mice and associated with outcome in patients, however, we lack an understanding for what might determine their differential abundance or functionality in situ. The underlying hypothesis of the proposed work is that maintaining TSL in the draining lymphatic basin will support systemic immune surveillance in patients. We therefore leverage our deep expertise in the lymphatic system, paired with new tools to track and perturb specialized T cell populations in the context of melanoma to generate mechanistic insights that can guide future strategies for clinical management of the lymphatic basin in the context of neoadjuvant therapy. We propose that understanding the mechanisms that maintain LN TSL will lead to new strategies to boost systemic immune surveillance. Successful completion of this work will aim to 1) map the differentiation trajectory of egressing CD8+ T cells as they seed draining LNs; 2) determine the dependence of TSL on lymphatic transport; and 3) define the TSL niche in mouse and human. We expect that the basic immunological insights generated here can be used to guide the application of neoadjuvant therapy in melanoma and other solid tumors. Further, this work will nominate new candidate targets or therapeutic schedules to improve local tumor control and protect against tumor recurrence and distant metastasis.