Extrafollicular plasma cells disable dendritic cell-T-cell priming in tumor-draining lymph nodes

Alberts, E.; Boulat, V.; Hung, M. S.; Xu, A. Q.; Quist, J.; Li, M.; Liu, F.; Wall, I.; Verghese, G.; Brundin, C. A.; Bhalla, A.; Jonsson, M.; Castellanos, C.; Rosekilly, J.; GILLETT, C.; Staaf, J.; e Sousa, C. R.; Karagiannis, S.; Grigoriadis, A.; Calado, D. P.

doi:10.64898/2026.04.20.719651

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bioRxiv · 10.64898/2026.04.20.719651

Extrafollicular plasma cells disable dendritic cell-T-cell priming in tumor-draining lymph nodes

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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 Fc{gamma} 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.

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Alberts, E., Boulat, V., Hung, M. S., Xu, A. Q., Quist, J., Li, M., Liu, F., Wall, I., Verghese, G., Brundin, C. A., Bhalla, A., Jonsson, M., Castellanos, C., Rosekilly, J., GILLETT, C., Staaf, J., e Sousa, C. R., Karagiannis, S., Grigoriadis, A., Calado, D. P.. 2026-04-22. Extrafollicular plasma cells disable dendritic cell-T-cell priming in tumor-draining lymph nodes. https://doi.org/10.64898/2026.04.20.719651

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