IGHA1 and IGHG1 expression panel predicts anti-PD-L1 response in muscle-invasive bladder cancer

Abstract Purpose B cells located in tertiary lymphoid structures (TLSs) may undergo clonal expansion, somatic hypermutation, isotype switching, and tumor-specific antibody production, suggesting that antibody-producing plasma cells may be involved in antitumor immunity. Methods This study used a combination of single-cell sequencing (5 samples from our center, and 4 samples from PRJNA662018) and spatial transcriptome (1 sample from our center, and 4 samples from GSE169379) research methods to investigate the relationship between TLSs and the immunoglobulin repertoire in muscle invasive bladder cancer (MIBC). 405 patients with MIBC from TCGA and 348 patients with metastatic urothelial carcinoma on PD-L1 inhibitor treatment from the IMvigor210 trial were included in this study. Results We identified IGHA1low IGHG1high patients could benefit more from cisplatin-based adjuvant chemotherapy and PD-L1 inhibitor. Further analyses revealed IGHA1low IGHG1high subgroup was linked to an antitumor immune microenvironment with highly immune effector cells. Spatial architecture unveils areas of B cell rich hot spots in TLS + tumors. We found that some IGHG1 clonotypes appeared inside the TLS, and most IGHG1 clonotypes were distributed in the tumor bed after treatment. The diversity of the immunoglobulin repertoire, especially IGHG1 clonotype, was higher after treatment. IGHA1low IGHG1high patients was associated with antitumor immune microenvironment and the therapeutic response to adjuvant chemotherapy and PD-L1 inhibitor in MIBC. Conclusion This study presents a spatial map of TLSs, where plasma cells of IGHG1 clonotypes mature within and disseminate around tumors. Plasma cells of IGHG1 clonotypes may cooperate with iCAF, macrophages and NK cells to kill tumor cells and improve the efficacy of immunotherapy.