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. 2019 Apr 12:11:2987-2995.
doi: 10.2147/CMAR.S191105. eCollection 2019.

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

Ming-Jun Shi  1   2 , Xiang-Yu Meng  3   4 , Qiu-Ji Wu  5 , Xiong-Hui Zhou  3
Affiliations

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

Ming-Jun Shi et al. Cancer Manag Res. .

Abstract

Background: 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. Materials and methods: 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. Results: We found that the CD3D/CD4 ratio was a stable independent prognostic factor in MIBC (beta = -0.87, P = 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, P = 2.67E-06). We also noted that the CD4 expression was significantly higher than CD3D (P < 0.05), indicating the presence of CD3-CD4+ cells which could be immune-suppressing. Conclusion: 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 CD3-CD4+ 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.

Keywords: CD3; CD4; CD8; basal-squamous subtype; bladder cancer; immunotherapy; muscle-invasive; prognosis; tumor-infiltrating lymphocytes.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Distribution of TIL markers and their ratios. (A) Distribution of CD3D, CD4 and CD8A; (B) distribution of CD3D/CD4 and CD3D/CD8A ratios. Abbreviation: TIL, tumor-infiltrating lymphocyte.
Figure 2
Figure 2
Kaplan–Meier curves showing difference in OS in MIBC patients between (A) low and high CD3D groups by median cutoff; (B) low and high CD3D groups by optimal cutoff; (C) low and high CD3D/CD4 groups by median cutoff; (D) low and high CD3D/CD4 groups by optimal cutoff. Abbreviation: MIBC, muscle-invasive bladder cancer.
Figure 3
Figure 3
Kaplan–Meier curves showing difference in OS in basal-squamous MIBC patients between (A) low and high CD3D groups by median cutoff; (B) low and high CD3D groups by optimal cutoff; (C) low and high CD3D/CD4 groups by median cutoff; (D) low and high CD3D/CD4 groups by optimal cutoff. Abbreviation: MIBC, muscle-invasive bladder cancer.
Figure 4
Figure 4
Forest plots of random-effects meta-analysis for CD3D/CD4 across cohorts. Abbrevaiton: TCGA, the Cancer Genome Atlas.
See this image and copyright information in PMC

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