Poor response to Bacillus Calmette-Guérin (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 pre-treatment immune microenvironment of NMIBC tumors can influence the response to intra-vesically 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 pre-treatment 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 non-responders. Chronic local inflammation, induced by the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) 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.
Cancer immunology research. 2024 Jun 25 [Epub ahead of print]
Priyanka Yolmo, Sadaf Rahimi, Stephen Chenard, Gwenaëlle Conseil, Danielle Jenkins, Kartik Sachdeva, Isaac Emon, Jake Hamilton, Minqi Xu, Manu Rangachari, Eva Michaud, Jose J Mansure, Wassim Kassouf, David M Berman, D Robert Siemens, Madhuri Koti
Queen's University, Kingston, Ontario, Canada., Queen's University Cancer Research Institute, Kingston, Ontario, Canada., Western University, London, Ontario, Canada., Queen's University, Kingston, ON, Canada., Université Laval, Quebec City, Quebec, Canada., McGill University, Montreal, Quebec, Canada., Research Institute of the McGill University Health Centre, Montreal, Canada., McGill University Health Centre, Montreal, Canada.