B cells disrupt tertiary lymphoid structure formation and suppress anti-tumor immunity
Changhao Chen, Mingjie An, Hanhao Zheng, Mingrui Pang, Pei Li, Xiayao Diao, Yuming Luo, Yan Lin, Daiyin Liu, Wenjie Li, Jiancheng Chen, Zhicong Liu, Zewei Chen, Andina Hu, Wenlong Zhong, Jian Huang, Tianxin Lin
Abstract
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.