Atypical B Cells Promote Cancer Progression and Poor Response to Bacillus Calmette-Guérin in Non - Muscle Invasive Bladder Cancer

Sep 21, 2026

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Poor response to Bacillus Calmette-Gurin (BCG) immunotherapy remains a major barrier in non–muscle invasive bladder cancer (NMIBC) management. This study examines how pretreatment immune microenvironments influence subsequent intravesical BCG efficacy and clarifies mechanisms of B cells in NMIBC. Findings show abundant B-cell–dominant tertiary lymphoid structures near the epithelium in BCG non-responders and higher immune-exhaustion–associated proteins within tumor-adjacent TLSs. Chronic inflammation drives formation and bladder infiltration of immunosuppressive atypical B cells, which accelerate progression and impair BCG response, especially in aging females.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

Introduction

Background on NMIBC and BCG immunotherapy

Risk factors and sex differences in bladder cancer

BCG treatment regimen and limitations

Rationale for studying atypical B cells and immune microenvironments

Atypical B Cells Promote Cancer Progression and Poor Response to Bacillus Calmette-Gurin in Non–Muscle Invasive Bladder Cancer Priyanka Yolmo1,2, Sadaf Rahimi1,2, Stephen Chenard1,2, Gwenalle Conseil1,2, Danielle Jenkins3, Kartik Sachdeva1,2, Isaac Emon1,2, Jake Hamilton1, Minqi Xu3, Manu Rangachari4, Eva Michaud5, Jose J. Mansure5, Wassim Kassouf5, David M. Berman2,3, David R. Siemens1,2,6, and Madhuri Koti1,2,6 | | | A | | B | S | | T | R | | A | | C | T | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Poor response to Bacillus Calmette-Gurin (BCG) immunotherapy remains a major barrier in the management of patients with non–muscle invasive bladder cancer (NMIBC) . Multiple factors are associated with poor outcomes, including biological aging and female sex. More recently, it has emerged that a B-cell–infiltrated pretreatment immune microenvironment of NMIBC tumors can influence the response to intravesically administered BCG. The mechanisms underlying the roles of B cells in NMIBC are poorly understood. Here, we show that B-cell–dominant tertiary lymphoid structures (TLSs), a hallmark feature of the chronic mucosal immune response, are abundant and located close to the epithelial compartment in pretreatment tumors from BCG non-responders. Digital spatial proteomic profiling of whole tumor
􀀶 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | sections from male and female patients with NMIBC who underwent treatment with intravesical BCG, revealed higher expression of immune exhaustion–associated proteins within the tumor-adjacent TLSs in both responders and nonresponders. Chronic local inflammation, induced by the N-butyl-N-(4-hydroxybutyl) nitrosamine carcinogen, led to TLS formation with recruitment and differentiation of the immunosuppressive atypical B-cell (ABC) subset within the bladder microenvironment, predominantly in aging female mice compared to their male counterparts. Depletion of ABCs simultaneous to BCG treatment delayed cancer progression in female mice. Our findings provide evidence indicating a role for ABCs in BCG response and will inform future development of therapies targeting the B-cell–exhaustion axis. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | Introduction Bladder cancer is the most common urological malignancy known worldwide with 573,278 cases diagnosed in 2020 (1) . The majority of patients with bladder cancer (75%–85%) are diagnosed with earlystage non–muscle invasive bladder cancer (NMIBC; ref. 2) . Exposure to environmental and occupational carcinogens, tobacco smoking, recurrent urinary tract infections, and aging can be attributed as the major risk factors for bladder cancer (3) . Although more common in males (2), females with bladder cancer generally present with advanced-stage tumors and experience shorter recurrence- and progression-free survival (4–7) . Following transurethral resection of 1Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Cana

FAQs

Why is poor response to BCG a critical issue in NMIBC?

Recurrence after BCG treatment occurs in more than 50% of patients, requiring repeated treatments, ongoing surveillance, and cystectomy when disease progresses to muscle-invasive cancer.

What role do pretreatment immune microenvironments play in BCG response?

The study reports that B-cell–infiltrated pretreatment immune microenvironments, including tertiary lymphoid structures, can influence how patients respond to intravesical BCG.

How do atypical B cells relate to cancer progression and BCG outcomes?

Chronic local inflammation promotes TLS formation and recruits immunosuppressive atypical B cells in the bladder microenvironment. Depleting atypical B cells alongside BCG delays cancer progression in female mice, supporting a functional role for these cells in BCG response.

Sep 21, 2026

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