The pre-treatment tumor microenvironment immune status determines Bacillus Calmette-Guerin immunotherapy response in early-stage bladder cancer.

Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy for early-stage bladder cancer (BCa), based on its immunostimulatory activity. However, over half of patients experience BCG failure and subsequent recurrence. The heterogeneity of the tumor microenvironment may influence BCG response, however this relationship is currently not well-established. We found that BCG response did not correlate with the number of tumor-infiltrating T cells but was determined by the pre-treatment immunosuppressive microenvironment. We identified a subset of cancer-associated fibroblasts characterized by microfibrillar-associated protein 2 (MFAP2+ CAF), which impaired BCG-induced antitumoral immunity by interacting with both individual T cells and tertiary lymphoid structures/lymphoid aggregates. This study also revealed a potential stepwise activation of cancer immune evasion factors based on cross-sectional analysis, from increasing MFAP2+ CAF to activation of PD-L1 and then LAG3 on T cells, during early-stage BCa development. These findings have the potential to enable accurate prediction of BCG response. This approach may also be applicable to the investigation of other human cancers.