Research Article: Prediction of intravesical recurrence of non-muscle-invasive bladder cancer by evaluation of intratumoral Foxp3+ T cells in the primary transurethral resection of bladder tumor specimens

Date Published: September 27, 2018

Publisher: Public Library of Science

Author(s): Ryosuke Murai, Yasushi Itoh, Susumu Kageyama, Misako Nakayama, Hirohito Ishigaki, Kazuo Teramoto, Mitsuhiro Narita, Tetsuya Yoshida, Keiji Tomita, Ken-ichi Kobayashi, Akinori Wada, Masayuki Nagasawa, Shigehisa Kubota, Kazumasa Ogasawara, Akihiro Kawauchi, Aamir Ahmad.


Patients with a history of non-muscle-invasive bladder cancer sometimes have recurrence of tumors after transurethral resection of bladder tumor treatment. To find factors related to the recurrence of non-muscle-invasive bladder cancer, we examined tissue specimens taken at transurethral resection of bladder tumor as an initial treatment. We revealed the association between prognosis of non-muscle-invasive bladder cancer and infiltration of Foxp3+ T cells that suppress anti-tumor immunity in 115 primary non-muscle-invasive bladder cancer patients retrospectively identified and followed for at least 3 months after primary transurethral resection. In immunohistological staining, we counted the number of cells positive for CD3 and positive for CD3 and Foxp3 together and calculated the percentage of Foxp3+ T cells among the CD3+ T cells. The recurrence-free survival rate was calculated by the Kaplan-Meier method, and a Cox regression analysis of recurrence factors was performed. The median (interquartile range) percentage of Foxp3+ T cells in all cases was 17.1% (11.9, 11.4–23.3%). Compared by risk stratification, it was 11.4% (10.4, 7.8–18.2%) in the low-risk group (n = 32), 16.8% (12.6, 11.6–24.2%) in the intermediate-risk group (n = 45), and 22.0% (9.7, 16.4–26.1%) in the high-risk group (n = 38). The Kaplan-Meier survival analysis indicated that the Foxp3+ T cell high group (≥ 17.1%) had a worse RFS rate than did the low group (< 17.1%) (P = 0.006). In multivariate analysis, the percentage of Foxp3+ T cells was an independent risk factor for intravesical recurrence (hazard ratio 2.25). Thus, peritumoral Foxp3+ T cell infiltration was correlated to risk stratification and recurrence-free survival. Therefore, the percentage of Foxp3+ T cells in tumor specimens may predict a risk for intravesical recurrence.

Partial Text

Bladder cancer is the eleventh most common cancer and the seventh most common in men who are newly diagnosed, according to a worldwide review [1]. Non-muscle-invasive bladder cancer (NMIBC) comprises 75% of primary bladder cancer cases and has a mortality rate that is lower than that of muscle-invasive bladder cancer. However, the 5-year-recurrence rates and 5-year-progression rates after treatment for NMIBC are in the ranges of 50% to 70% and 10% to 30%, respectively [2]. Since the high recurrence rate in NMIBC impairs the quality of life in many patients, reducing the recurrence rate is clinically important. Therefore, we need to find a new biomarker to classify patients who may have a high recurrence risk.

In the present study, we performed a quantitative analysis on infiltration of Treg cells in the NMIBC tissue and revealed a relationship between the percentage of Treg cells in the tumor tissue and the recurrence rate after TURBT of NMIBC: the high frequency of recurrent bladder cancer was observed in patients whose TURBT specimens contained a high percentage of Foxp3+CD3+ cells. This observation suggests that Foxp3+CD3+ cells around the tumor contribute to tumor progression. Furthermore, our results indicate that NMIBC induces accumulation of Treg cells around the tumor tissue because the percentage of Foxp3+ cells among the CD3+ cells in TURBT specimens was higher than that in normal bladder tissue.

The percentage of Foxp3+ T cells in specimens of NMIBC taken at TURBT was significantly associated with the recurrence free survival rate and was suggested as a useful prognostic indicator.




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