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

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.

Analysis of the treg cell population in the peripheral blood of ovarian cancer patients in relation to the long-term outcomes

“…Increasing the FoxP3+/CD4+ ration of TIL seems to be an independent adverse prognostic factor in a hormone receptor positive group of patients, mainly in a luminal A subtype of breast cancer [21]. Analyses of patients with lung [7], urinary bladder [8] and ovarian cancers [9,10] yielded similar results, confirming the relationship between Treg cell population size and cancer stage.…”

“…Recently, it has been proven that in patients with sometypes of cancers (for example, breast [6], lung [7], urinary bladder [8], and ovarian cancers [9,10] the Treg cell subpopulation size correlates withan advanced stage of cancer. However, there is no such correlation with the histological tumor type, for instance, squamous vs adenocarcinoma in patients with lung cancer [7] and mucinous vs serous adenocarcinoma in patients with ovarian cancer [10].…”

Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer

“…Another trial showed that a low CD4+CD25+FOXP3+ Treg frequency after radical cystectomy in pT2-pT4 tumors was associated with poor survival. The authors think that this post-surgery Treg decrease may indicate a tumor-specific immune tolerance during tumor advancement [41]. Moreover, Tregs can suppress effector mechansims of the immune response in a variety of vaccination models [42–44].…”

Expression of PD-L1 in tumor and immune system cells affects the survival of patients with urinary bladder cancer

“…Recent studies have indicated several probable mechanisms of tumor progression by the way of modulating the immune system anti-tumor response. One important mechanism is the suppression of anti-tumor response by an excess infiltration of regulatory T cells (Tregs) [9]. The over-expression of RCAS1 in tumor cells (TCs) and the surrounding cells of the cancer microenvironment were also shown to correlate with clinical and pathomorphological patterns of malignancy [5].…”