CD163+ Macrophages Orchestrate Tumor Immunity By Spatially Fortifying Follicular Lymphoma Against CD8+ T Cells Attack during Early Progression

B ack ground: The tumor immune microenvironment (TIME) plays a pivotal role in the development and progression of follicular lymphoma (FL). However, the evolution of TIME during progression of disease within 24 months (POD24) remains poorly understood. Methods: We employed imaging mass cytometry with a panel of 36 meta-tagged antibodies to examine the immune architecture of lymph nodes from 13 FL patients, both at diagnosis and during POD24. Results: Our analysis revealed a decrease in immune infiltration from the peri-follicular regions towards the follicular centers in FL. Notably, there was an increase in CD163+ macrophages within the follicles, accompanied by an upregulation of PD-1 ligands during POD24. Spatial analysis showed that FL cells tend to evade immune attacks not merely through spatial separation from CD8+ T cells but by proactively recruiting immunosuppressive cells prior to encountering these T cells. Furthermore, during POD24, more CD8+ T cells in proximity to FL cells were found interacting with macrophages rather than regulatory T cells (Tregs). There was also an observed increase in the cooperation between macrophages and Tregs, which collectively worked to subdue cytotoxic T cell activity, thereby creating a more immunosuppressed environment. Conclusions: FL cells exhibit more aggressive evasion tactics and exist within a more immunosuppressive microenvironment during POD24. These findings suggest that immunotherapeutic strategies targeting PD-1, macrophages, and CTLA-4 may hold promise for improving outcomes in FL patients experiencing early progression.