FCRL5 expressing B cell expansion associates with poor response to Bacillus Calmette-Guérin immunotherapy in patients with non-muscle invasive bladder cancer

Majority of patients treated with Bacillus Calmette–Guérin (BCG) immunotherapy, for non-muscle invasive bladder cancer (NMIBC), experience early recurrence. Building upon our previous findings showing the pathogenic role of atypical B cells (ABCs) in cancer progression, and following intravesical treatment with BCG, in an aging murine model of bladder cancer, we conducted a longitudinal study to characterize B cell associated local and systemic responses in 45 patients with high-risk NMIBC who underwent treatment with BCG. Single cell spatial transcriptomic analysis and immunophenotyping of corresponding tumors revealed enrichment of ABCs within tumor-stroma and tertiary lymphoid structures, where they co-localized with PD-1⁺ B cells, regulatory T cells, and CD163⁺ macrophages. BCG non-responders exhibited expanded IgG autoantibody repertoires, progressive IgG reactivity against BCG antigens, and higher tumor IgG deposition. Independent validation in two patient cohorts (total n = 409), revealed a significant association between high expression of the ABC specific, FCRL5 , and poor outcomes. Our study identifies ABCs as key regulators of local and systemic humoral immune dysfunction in high-risk NMIBC.