B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity
Menée à l'aide de lignées cellulaires, de modèles murins ainsi que d'échantillons sanguins, d'échantillons tumoraux et d'échantillons tissulaires adjacents prélevés sur des patients atteints d'un cancer de la vessie, cette étude met en évidence un mécanisme par lequel une sous-population de lymphocytes B exprimant l'immunoglobuline IGLL5 empêche la formation d'une structure lymphoïde tertiaire et supprime l'immunité antitumorale
Tertiary lymphoid structures (TLSs) promote antigen-specific anti-tumor immunity, but the regulators of TLSs homeostasis in cancer remain unclear. Using single-cell RNA-sequencing and spatial transcriptomics, we identify an IGLL5+ B cell subset in bladder cancer (BCa). In genetically engineered and humanized mouse models, these IGLL5+ B cells disrupt TLS's integrity and impair immunotherapy responses. Mechanistically, IGLL5+ B cells bind high endothelial venules (HEVs) via IGLL5-LT
βR ligand-receptor interactions, with IGLL5 inducing a conformational change in LTβR that inhibits non-canonical NF-κB signaling, leading to TLSs disassembly. Clinically, blocking IGLL5 preserves TLSs and enhances immunotherapy efficacy in patient-derived xenograft (PDX) and pan-cancer models. Our findings suggest that targeting IGLL5+ B cells offers a promising strategy to boost TLS-dependent cancer immunotherapy.
Cancer Cell , article en libre accès, 2026