Fitness and immune-escape within germinal centers shape premalignant evolution toward lymphoma

Zhang, L.; Hung, M. S.; Atkins, O.; Artemov, P.; Sochon, A.; Boulat, V.; Kashkar, H.; Reinhardt, H. C.; Fitzgibbon, J.; Okosun, J.; Calado, D. P.

doi:10.64898/2026.06.25.734549

bioRxiv · 10.64898/2026.06.25.734549

Fitness and immune-escape within germinal centers shape premalignant evolution toward lymphoma

Zhang, L.·Hung, M. S.·Atkins, O.·Artemov, P.·Sochon, A.·Boulat, V.·Kashkar, H.·Reinhardt, H. C.·Fitzgibbon, J.·Okosun, J.·Calado, D. P.

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Abstract

Germinal centers (GCs) support physiological B-cell mutagenesis and are considered lymphoma-permissive; nevertheless, lymphoma development is uncommon. Human in situ follicular neoplasia (ISFN) captures this paradox: premalignant B-cells can persist within GCs for prolonged periods without progressing to overt lymphoma. We found that human ISFN, but not normal GCs, are infiltrated by CD8 T-cells, suggesting that premalignant GC B-cells are locally immune-surveilled. Using mouse models that separate early premalignant fitness from lymphoma-associated evolution, we show that fitness-enhanced premalignant GC B-cells expand transiently but are selectively eliminated by infiltrating cytotoxic CD8 T-cells, while normal GC B-cells are spared. By contrast, evolved premalignant GC B-cells retain their fitness but disable productive CD8 T-cell cytotoxic differentiation, allowing persistence and lymphoma-like transcriptional and genomic evolution. These findings establish GCs as active immune-surveillance sites and show that progression from premalignancy to lymphoma requires both enhanced GC fitness and escape from local immune control. Key findingsGCs undergo active immune-surveillance to detect premalignant B-cells. Premalignant GC B-cells trigger cytotoxic CD8 T-cell responses. Lymphoma-associated evolution enables immune-escape within GCs. Fitness and immune-escape drive evolution from premalignancy to lymphoma. BlurbGerminal centers are considered lymphoma-permissive; however, progression from premalignancy is uncommon. Using models of human in situ follicular neoplasia, Zhang et al. demonstrate that infiltrating CD8 T-cells actively eliminate premalignant GC B-cells. Co-occurrence of lymphoma-like alterations blocks this cytotoxic T-cell response, driving immune escape and lymphoma evolution.

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Zhang, L., Hung, M. S., Atkins, O., Artemov, P., Sochon, A., Boulat, V., Kashkar, H., Reinhardt, H. C., Fitzgibbon, J., Okosun, J., Calado, D. P.. 2026-06-26. Fitness and immune-escape within germinal centers shape premalignant evolution toward lymphoma. https://doi.org/10.64898/2026.06.25.734549

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