IGLL5+ B Cells Inhibit Vasculature and Impair Tertiary Lymphoid Structures

Tertiary lymphoid structures (TLS) promote antitumor immunity and immunotherapy response. Accordingly, strategies that facilitate TLS formation in immunotherapy-resistant tumors may restore therapeutic sensitivity, yet the mechanisms governing TLS development and maintenance remain incompletely defined. In a recent study, Chen, An, Zheng, Pang, Li, and colleagues investigated regulators of TLS abundance in bladder cancer and identified a distinct B-cell subset characterized by elevated IGLL5 expression that was inversely associated with TLS density and correlated with poor clinical outcomes. IGLL5+ B cells preferentially localized to high endothelial venules (HEV), where they disrupted lymphocyte recruitment and retention. Mechanistic analyses revealed a direct interaction between IGLL5 and lymphotoxin-β receptor (LTβR) that occurred selectively at LTβR+ HEVs within mature TLSs. This specificity was driven by chemokine signaling, with increased CCL19 production by LTβR+ HEVs and elevated expression of its receptor, CCLR2, in IGLL5+ B cells. Functionally, IGLL5 inhibited noncanonical NFκB signaling in HEVs, a pathway normally required for HEV maturation and lymphocyte trafficking. By outcompeting the physiological ligand LTα1β2, IGLL5 disrupted LTβR-dependent signaling, suppressed downstream NIK activity, and altered HEV structure. As a result, HEVs adopted an abnormally dilated phenotype, leading to impaired lymphocyte recruitment and reduced CD8+ T-cell effector function within TLSs. Importantly, these defects were reversible following activation of noncanonical NFκB signaling using LTβR agonists or CD40L. In vivo, elevated IGLL5+ B-cell abundance was associated with dysfunctional HEVs, reduced TLS formation, diminished CD8+ T-cell infiltration, and poor responses to immune checkpoint blockade, while IGLL5-neutralizing antibodies improved responses in humanized patient-derived xenograft models. Clinically, validation in pan-cancer cohorts supported the relationship between IGLL5+ B cells with HEVs and TLSs observed in vivo. Collectively, this work defines a B cell–mediated mechanism that disrupts TLS homeostasis and establishes the IGLL5–LTβR axis as a therapeutically actionable target to enhance immunotherapy responsiveness.Chen C, An M, Zheng H, Pang M, Li Y, Diao X, et al. B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity. Cancer Cell 2026 Jan 8 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.