Many solid cancers, including melanoma, eventually spread to tumour-draining lymph nodes (LNs). As LNs are sites where spontaneous and therapy-associated immune responses against cancer are initiated and sustained, understanding how disease control is impacted by metastatic spread to this unique site is critically important. Despite this, the cellular and molecular mechanisms involved remain unresolved due to a paucity of suitable preclinical models. To address this, our group established a translatable mouse melanoma model, whereby a proportion of mice develop spontaneous metastases in the tumour-draining LN despite surgical excision of the primary skin tumour.
In this project, we treated lymph node metastases with in vitro-activated tumour-specific CD8+ T cells as adoptive T cell therapy (ACT). This treatment resulted in stable disease control over several weeks in a proportion of mice, whereas others resisted therapy and escaped. To understand mechanisms of ACT-induced tumour control, we characterised responses in stably controlled compared to escaped metastases with various cutting-edge high-dimensional analysis platforms. Spatial profiling using CODEX imaging showed controlled tumours exhibit stronger activated T cell infiltration and maintain stem-like T cells in surrounding lymphoid tissue known to be important in sustaining responses. Further analysis of transferred T cells revealed cell populations with phenotypic and transcriptomic features unique to only one disease outcome. Interestingly, trajectory analysis predicted distinct differentiation pathways, with escaped but not controlled tumours displaying features of classical T cell exhaustion. Indeed, we identified >600 differentially expressed genes (DEGs) between the two groups, with less exhaustion and greater stemness-related genes in ongoing control.
This work has provided a highly novel description of the features key to ACT-induced control of metastatic LNs. We intend to next modulate the expression of certain DEGs identified in this analysis to improve ACT-induced control of solid tumours, an outcome that has proven clinically challenging to achieve.