Sexual Dimorphism in Outcomes of Non-muscle-invasive Bladder Cancer: A Role of CD163+ Macrophages, B cells, and PD-L1 Immune Checkpoint.

backgroundNon-muscle-invasive bladder cancer (NMIBC) is over three times as common in men as it is in women; however, female patients do not respond as well to immunotherapeutic treatments and experience worse clinical outcomes than their male counterparts. Based on the established sexual dimorphism in mucosal immune responses, we hypothesized that the tumor immune microenvironment of bladder cancer differs between the sexes, and this may contribute to discrepancies in clinical outcomes.

objectiveTo determine biological sex-associated differences in the expression of immune regulatory genes and spatial organization of immune cells in tumors from NMIBC patients. DESIGN SETTING AND

participantsImmune regulatory gene expression levels in tumors from male ( OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Transcriptome sequencing data were analyzed using DESeq2 in R v4.0.1, followed by application of the Kruskal-Wallis test to determine gene expression differences between tumors from males and females. Immunofluorescence data analyses were conducted using R version 3.5.3. Survival analysis was performed using survminer packages. RESULTS AND LIMITATIONS: High-grade tumors from female patients exhibited significantly increased expression of B-cell recruitment (

conclusionsThese novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials in NMIBC. PATIENT SUMMARY: In this study, we measured the abundance of various immune cell types between tumors from male and female patients with non-muscle-invasive bladder cancer. We demonstrate that tumors from female patients have a significantly higher abundance of immunosuppressive macrophages that express CD163. Higher abundance of tumor-associated CD163-expressing macrophages and B cells is associated with shorter recurrence-free survival in both male and female patients.