Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Abstract

Non-muscle invasive bladder cancer (NMIBC) is significantly more common in men than women. However, female patients with NMIBC often present with more aggressive disease and do not respond as well to immunotherapy treatments. We hypothesized that sexual dimorphism in the tumor immune microenvironment (TIME) may contribute to the inferior clinical outcomes observed in female patients. To test this hypothesis, we interrogated the expression patterns of genes associated with specific immune cell types and immune regulatory pathways using tumor whole transcriptome profiles from male (n=357) and female (n=103) patients with NMIBC. High-grade tumors from female patients exhibited significantly increased expression of CD40, CTLA4, PDCD1, LAG3 and ICOS immune checkpoint genes. Based on the significant differences in expression profiles of these genes and the cell types that most commonly express these in the TIME, we evaluated the density and spatial distribution of CD8+Ki67+ (activated cytotoxic T cells), FoxP3+ (regulatory T cells), CD103+ (tissue resident T cells), CD163+ (M2-like tumor associated macrophages), CD79a+ (B cells), PD-L1+ (Programmed-Death Ligand-1) and PD-1+ cells using multiplexed immunofluorescence in an independent cohort of 332 patient tumors on a tissue microarray (n=259 males and n=73 females). Tumors from female patients showed significantly higher infiltration of CD163+ macrophages and PD-L1+ cells compared to tumors from male patients. Notably, increased infiltration of CD163+ macrophages and CD79a+ B cells independently associated with decreased recurrence free survival. Not only do these results have the potential to inform the rational utilization of immunomodulatory therapies based on the TIME of both male and female patients with NMIBC, these novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials.

Tumor-Infiltrating B- and T-Cell Repertoire in Pancreatic Cancer Associated With Host and Tumor Features

“…Although the differences were nominally significant, we observed a higher amount of IGK expression in females. Similarly, a recent finding reported an increased expression of immune checkpoint genes, and those associated with B-cell recruitment and function, in high-grade bladder cancer tumors from females compared to those from males (39). Interestingly, we observed approximately 40-fold differences between tumor and normal samples regarding the number of IG reads.…”

Tumor-associated macrophages and PD-L1 in prostate cancer: a possible key to unlocking immunotherapy efficacy

“…Consistently, in cervical cancer and oral carcinomas, high levels of CD163+ TAMs infiltration were also associated with worse disease-free survival (DFS) [10,30,31]. Accumulated evidence suggests that a higher CD163+ TAMs count indicates poor prognosis and high metastatic potential in various cancers [32]; however, how CD163 works in the protumoral activation of TAMs remains unclear. Our data showed that the infiltration levels of M2-TAMs were significantly associated with Gleason score and the prognosis of PCa patients.…”