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

Area of Science:

• Oncology
• Immunology
• Urology

Background:

• Bacillus Calmette-Guérin (BCG) immunotherapy is a standard treatment for non-muscle invasive bladder cancer (NMIBC).
• Poor response to BCG remains a significant challenge in NMIBC management.
• B-cell infiltration in the tumor microenvironment influences BCG treatment outcomes.

Purpose of the Study:

• To investigate the role of B cells and tertiary lymphoid structures (TLSs) in BCG response in NMIBC.
• To elucidate the mechanisms by which B cells affect BCG immunotherapy efficacy.
• To identify potential therapeutic targets within the B-cell immune axis.

Main Methods:

• Digital spatial proteomic profiling of NMIBC tumor sections from patients treated with BCG.
• Analysis of B-cell-dominant TLSs in pretreatment tumors.
• Murine model of bladder cancer with induced chronic inflammation to study TLS formation and B-cell subsets.
• Experimental depletion of atypical B cells (ABCs) in conjunction with BCG treatment in mice.

Main Results:

• B-cell-dominant TLSs were abundant near the epithelium in tumors from BCG non-responders.
• Immune exhaustion-associated proteins were upregulated in TLSs adjacent to tumors in both BCG responders and non-responders.
• Chronic inflammation induced TLS formation and promoted immunosuppressive ABC differentiation, particularly in aging female mice.
• Depletion of ABCs alongside BCG treatment improved cancer progression outcomes in female mice.

Conclusions:

• Atypical B cells (ABCs) play a crucial role in the response to BCG immunotherapy in NMIBC.
• The B-cell-exhaustion axis represents a potential therapeutic target for improving BCG efficacy.
• Understanding the B-cell microenvironment is vital for developing novel NMIBC treatment strategies.