Luyang Zhang

Bacillus Calmette–Guérin (BCG) is the standard adjuvant therapy for early-stage bladder cancer, based on its immunostimulatory activity. However, more than 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 pretreatment 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 programmed cell death ligand 1 and then lymphocyte-activation gene 3 on T cells during early-stage bladder cancer 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.

Supplementary Data File S1 from The Pretreatment Tumor Microenvironment Immune Status Determines Bacillus Calmette–Guerin Immunotherapy Response in Early-Stage Bladder Cancer

Supplementary Figure S3. PD-L1 and LAG3 are activated in response to specific microenvironment parameters.

Supplementary Figure S1. MFAP2+ CAF density is an independent prognostic factor in BCG-treated patients.

Supplementary Figure S2. MFAP2+ cells are a distinct subset of PDGFRA+ CAFs that impairs T cell function.

Supplementary Figure S4. MFAP2+ CAFs originate from mesenchymal stem cells.

Supplementary Figure S5. MFAP2+ CAFs suppress CD3+ T cell function during in vitro co-culture.