Frequency of CD4+CD25+Foxp3+ cells in peripheral blood in relation to urinary bladder cancer malignancy indicators before and after surgical removal.

Wojciech Jóźwicki,Jerzy Siekiera,Anna A Brożyna,Andrzej T Slominski

doi:10.18632/oncotarget.7199

Wojciech Jóźwicki, Jerzy Siekiera + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.7199

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Abstract

Tumor cells communicate with stromal cells, including cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), to form microenvironment inhibiting immune responses. Regulatory T cells (Tregs, CD4+CD25+FoxP3+) stimulate immune tolerance and facilitate tumor progression. We analyzed the changes in Treg frequencies assessed using flow cytometry in the peripheral blood of patients with urothelial bladder cancer before and after tumor-removal. Changes in Treg frequency were investigated in relation to clinicopathomorphological indicators of tumor malignancy and expression of RCAS1 on CAFs and TAMs. Higher Treg frequencies were observed in early phase of tumor growth (pTa-pT2), in larger tumors, with more aggressive type of invasion, and with expression of RCAS1. The later phase of tumor development, accompanied by a nonclassic differentiations and pT3-pT4 advancement, had lower number of tumor infiltrating lymphocytes (TILs) and lower Treg frequency. Furthermore, in pT2-pT4 tumors, a decreased post-surgery Treg frequency was associated with poorer prognosis: patients with the lowest frequency of Tregs died first. These findings strongly suggest that the Treg frequencies at later phase of tumor growth, associated with a low anti-tumor response, represent a new and important prognostic indicator in urinary bladder cancer.

Highlights

One of the most important characteristics of tumor cells is their ability to escape the immune surveillance through inhibition of immune responses, and induction of immunological tolerance [1,2,3]
Tumor cells communicate with stromal cells, including cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), to form a specific microenvironment that provides a niche that facilitates tumor growth and progression [4]
We observed higher Treg-pre frequency compared with Treg-post early frequency in peripheral blood of all patients with urothelial bladder cancer, regardless of its progression (Figure 1A), which is consistent with the findings on other tumors, such as esophageal, gastrointestinal, pancreatic and breast cancers, and myeloid leukemia, as described in the literature [reviewed in [27], 15, 29]

Summary

Introduction

One of the most important characteristics of tumor cells is their ability to escape the immune surveillance through inhibition of immune responses, and induction of immunological tolerance [1,2,3]. The expression of the receptor-binding cancer antigen present on SiSo cells (RCAS1) in the bladder cancer associated CAFs and TAMs is associated with a poor prognosis [7, 8, 9] This phenomenon appears to be dependent on the RCAS1 modulation of local immunological tolerance, enabling tumor cells to escape the immune surveillance and leading to tumor progression [10, 11]. The specific aim of our study was analyzing the blood Treg frequency in relation to pathomorphological markers of malignancy, such as grade (G), pT, TIT, NDN, metastasis, tumor size, and the likelihood of death as well as in relation to the expression of RCAS1 in tumor cells and in TAMs and CAFs. In this study, we attempted to obtain potentially significant information about fluctuations in peripheral blood Treg frequency in relation to urinary bladder cancer malignancy, before and after surgery

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