B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity

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-LTβR 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. • IGLL5 is highly expressed in the B cell subset identified in TLSs deficient bladder cancer • IGLL5 + B cells disarray TLSs homeostasis in genetically engineered and humanized mice • IGLL5 + B cells disrupt HEVs' functional phenotype via IGLL5-LTβR interplay • Targeting IGLL5 + B cells promotes TLSs formation and enhances tumor immunotherapy Chen et al. find that a specific B cell subset is associated with immunotherapy resistance in bladder cancer. IGLL5 + B cells interact with HEVs through IGLL5-LTβR signaling, leading to the impairment of TLSs formation in humanized mouse models. This interaction presents a promising therapeutic target for overcoming immunotherapy resistance in bladder cancer.