Integration of CD4+ T cells and molecular subtype predicts benefit from PD‐L1 blockade in muscle‐invasive bladder cancer

Abstract Muscle‐invasive bladder cancer (MIBC) is a disease characterized by molecular and clinical heterogeneity, posing challenges in selecting the most appropriate treatment in clinical settings. Considering the significant role of CD4 + T cells, there is an emerging need to integrate CD4 + T cells with molecular subtypes to refine classification. We conducted a comprehensive study involving 895 MIBC patients from four independent cohorts. The Zhongshan Hospital (ZSHS) and The Cancer Genome Atlas (TCGA) cohorts were included to investigate chemotherapeutic response. The IMvigor210 cohort was included to assess the immunotherapeutic response. NCT03179943 was used to evaluate the clinical response to a combination of immune checkpoint blockade (ICB) and chemotherapy. Additionally, we evaluated genomic characteristics and the immune microenvironment to gain deeper insights into the distinctive features of each subtype. We unveiled four immune‐molecular subtypes, each exhibiting distinct clinical outcomes and molecular characteristics. These subtypes include luminal CD4 + T high , which demonstrated benefits from both immunotherapy and chemotherapy; luminal CD4 + T low , characterized by the highest level of fibroblast growth factor receptor 3 ( FGFR3) mutation, thus indicating potential responsiveness to FGFR inhibitors; basal CD4 + T high , which could benefit from a combination of ICB and chemotherapy; and basal CD4 + T low , characterized by an immune suppression microenvironment and likely to benefit from transforming growth factor‐β (TGF‐β) inhibition. This immune‐molecular classification offers new possibilities for optimizing therapeutic interventions in MIBC.