Neoadjuvant immunotherapy (NeoIT) has emerged as a transformative strategy in the treatment of early-stage non-small cell lung cancer (NSCLC), yet the role of tumour-draining lymph nodes (tdLNs) in mediating this response is often overlooked. Historically, lymph nodes have been dissected during surgery for metastatic cancers, but recent insights suggest that preserving these nodes may enhance treatment efficacy. The lymph nodes serve as critical hubs for immune activation, orchestrating interactions between various immune populations essential for a robust anti-tumor response. Conventional approaches aimed at discovering new immunotherapy drug targets or defining molecular biomarkers, which predict the likelihood of recurrence in NeoIT-treated patients, have relied on analysis of the localized tumour microenvironment. Given the possible role of the tdLN in orchestrating the immune response to immunotherapy, a multi-modal analysis of spatially-oriented changes in the tdLN immune and stromal compartments is warranted.
This study investigates the immune dynamics within tdLNs from NSCLC patients participating in the POPCORN clinical trial, a phase Ib/II study comparing anti-PD-1 (nivolumab) with a combination of anti-PD-1 and anti-RANKL (denosumab), administered pre-operatively to patients with operable stage IB-IIIA disease. Utilizing advanced spatial transcriptomics and proteomics platforms such as NanoString CosMx, GeoMx and the Akoya/CODEX platform, we aim to elucidate how NeoIT influences the spatial organization and immune interactions within tdLNs. In order to inform mechanisms of drug response, our analysis focused not only on differentially-expressed transcripts within key immune anatomic units of the LN (follicle and paracortex) but also spatially-constrained cell-cell and ligand-receptor interactions across the entire LN tissue.
Our findings indicate that NeoIT induces the remodeling of lymph node architecture, characterized by changes in stromal and endothelial cells, indicating altered scaffold and vasculature, alongside variations in immune populations such as macrophages and dendritic cells. Additionally, analysis of cell-cell interactions reveals shifts in communication among these populations, highlighting a complex reorganization of immune dynamics.
Understanding these mechanisms is essential for optimizing therapeutic strategies, developing informed strategies for patient surveillance and improving patient outcomes. By revealing key immune interactions and pathways that drive treatment efficacy, this research underscores the critical role of tdLNs in the immunotherapy landscape and advocates for a paradigm shift in lymph node management during surgical interventions.