High CD3D/CD4 ratio predicts better survival in muscle-invasive bladder cancer.

Bladder cancer is a common malignancy that affects the human urinary tract. Muscle-invasive bladder cancer (MIBC) is aggressive and has poor prognosis. Previous studies have reported that the tumor-infiltrating lymphocytes (TILs) were associated with MIBC outcome; however, inconsistency remains and mRNA level TIL markers' prognostic significance in MIBC is unclear.  In the present study, we reanalyzed data from four public datasets (the Cancer Genome Atlas for investigation; and CIT, GSE5287, and GSE31684 for validation) to examine the prognostic significance of CD3D, CD4, CD8A, CD3D/CD4 and CD3D/CD8A in MIBC.  We found that the CD3D/CD4 ratio was a stable independent prognostic factor in MIBC (beta = -0.87, = 0.025); high CD3D/CD4 ratio predicted better survival in MIBC, and the power of this association was much stronger in basal-squamous tumors (beta = -4.73, = 2.67E-06). We also noted that the CD4 expression was significantly higher than CD3D (< 0.05), indicating the presence of CD3CD4 cells which could be immune-suppressing. The CD3D/CD4 ratio can be viewed as a prognostic marker and a rough measurement for the interaction between immune-effecting CD3 TILs and immune-suppressing CD3CD4 cells in MIBC, and this interaction may play a particularly important role in anti-cancer immunity in basal-squamous tumors as it has a very strong association with survival in this subtype, and may be used to select potential responders to immunotherapy.