Extrafollicular plasma cells disable dendritic cell-T-cell priming in tumor-draining lymph nodes
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
How plasma cells (PCs) shape anti-tumor immunity is unclear. We hypothesized that conflicting prognostic associations reflect differences in immune context and PC ontogeny. We identify extrafollicular (EF)-PCs as an antibody-independent checkpoint that aborts priming by disabling the cDC1→CD8 + T-cell axis in tumor-draining lymph nodes (td-LNs). EF-PCs blunt cDC1 activation and CCR7-guided repositioning into T-cell zones, precluding formation of TCF1⁺ stem-like CD8⁺ T-cells. Depleting EF-PCs in vivo restores cDC1 trafficking, expands the stem-like reservoir, increases intratumoral CD8⁺ infiltration, and restrains tumor growth; benefit is lost with CD8 T-cell ablation. Neither serum transfer nor Fcγ receptor blockade reverses tumor control, supporting a non-canonical, antibody-independent mechanism. Across independent triple-negative breast cancer cohorts, we find EF-PC hyperplasia in td-LNs and tumors; and within immune-cold cases, EF-PC burden stratifies poor prognosis and metastatic risk. A cross-species EF-PC signature maps to a conserved PC-state across cancer types that is linked to poor outcome and immune-checkpoint blockade resistance. EF-PCs thus relocate the dominant failure point to td-LNs and offer a tractable upstream target to convert immune-cold tumors into immune-responsive disease.
