Tumor-infiltrating CD8+ lymphocytes predict different clinical outcomes in organ- and non-organ-confined urothelial carcinoma of the bladder following radical cystectomy

Abstract

Tumor-infiltrating lymphocytes (TILs) are associated with better clinical outcomes in many tumors. TILs represent a cell-mediated immune response against the carcinoma. CD8+ TILs are a crucial component of cell-mediated immunity. The significance of CD8+ TILs has not been reported respectively in organ- and non-organ-confined urothelial carcinoma (UC) of the bladder. We explored the prognostic value of CD8+ TILs in the two groups. The presence of CD8+ TILs was assessed by immunohistochemical staining of whole tissue sections from 75 organ and 51 non-organ-confined disease patients with long-term follow-up, and its correlation with clinicopathological features and overall survival (OS) was determined. The CD8+ TIL immunohistochemical staining score was 0 (<1%), 1 (≥1%), 2 (≥5%), or 3 (≥10%) based on the percentage of positively stained cells out of total cells. A patient was considered CD8 negative if the score was 0. There were no associations between CD8+ TILs and age, sex, nuclear grade, and adjuvant or neoadjuvant chemotherapy in organ- and non-organ-confined disease. The presence of CD8+ TILs was seen more frequently in pTa-₁ than pT₂ stage (p = 0.033) in organ-confined disease. No associations between CD8+ TILs and pT stage, pN stage were found in non-organ-confined disease. CD8+ TILs were associated with better OS (log-rank test, P = 0.036) in non-organ-confined disease, but with poorer OS (log-rank test, P = 0.040) in organ-confined disease by the Kaplan-Meier method. In multivariate analysis, CD8+ TILs were an independent favorable prognostic factor in non-organ-confined disease, but were an independent unfavorable prognostic factor in organ-confined disease. These results suggest that CD8+ TILs have clinically significant anti-tumor activity in non-organ-confined disease, but may have pro-tumor activity in organ-confined disease. Therefore, we should be cautious if CD8+ TILs are aimed to be exploited in the treatment of bladder cancer.

Keywords: CD8+ TILs; Non-organ-confined disease; Organ-confined disease; Urothelial carcinoma of the bladder.

Figure 1. Representative examples of CD8+ TILs immunostaining.

CD8+ TILs are distributed mainly at the interface of the tumor and tumor-adjacent stroma. (A), (B), (C) and (D) (×100 magnification) are representative images of scores of 0, 1, 2, and 3, respectively.

Figure 2. Kaplan–Meier survival curves with log-rank testing.

(A) All UC of the bladder (CD8+, 90; CD8−, 36). (B) Non–organ-confined UC of the bladder (CD8+, 35; CD8−, 16). (C) Organ-confined UC of the bladder (CD8+, 55; CD8−, 20).