Global analysis of cancers revealed the importance of the adaptive immune cell response against tumors for cancer patient survival. However, the clinical outcome depends on the nature, functional orientation, density and location of immune cells within the tumor microenvironment [
1]. For instance, ample clinical evidence shows that longer survival of cancer patients is associated with increased expression of genes characteristic of type 1 effector T cells, in particular the T-box master transcription factor regulator (T-bet) [
2,
3]. Although T-bet is the master regulator of Th1 cell differentiation, it is expressed in multiple cells of the innate and adaptive immune system, including innate lymphoid cells (ILCs) [
4,
5]. CD8
+-infiltrating lymphocytes are also predictive of survival in muscle-invasive urothelial carcinoma [
6] and are associated with a favorable prognosis in ovarian cancer [
7]. This contrasts with the accumulation of tumor-infiltrating regulatory T cells (Tregs), where it is attested that the master regulator of Treg differentiation Foxp-3 is expressed. This creates an immunosuppressive microenvironment leading to tumor progression [
8]. This is due to the ability of Treg cells to dampen the activity of CD4
+ and CD8
+ T cells, as well as natural killer (NK) cells, mainly by the release of transforming growth factor β (TGFβ1) and IL-10 [
9]. Other adaptive cells are differently associated to cancer patient outcome. The Th2 response, evidenced inter alia by the expression of GATA-3, was associated with tumor immune evasion in a mouse study [
10], but was not associated with a clinical outcome in human studies [
11,
12] or in patient’s prognosis [
13]. Patients with a low Th17 response had a better disease-free survival [
13], whereas Th17 cells increased with advanced gastric cancer [
14]. The opposite effect was observed for ovarian cancer [
15]. Concerning follicular helper T cells (Tfh), an additional effector subset of T helper lymphocytes whose development is controlled by the B-cell lymphoma 6 transcription factor (Bcl-6), the presence of Tfh was high in various human cancers including malignancies in the lymphoid system [
16]. Where the Tfh presence is significant, it has been associated with a better patient cancer outcome (breast cancer) [
17], whereas a decreased proportion of Tfh was associated with increased hepatocellular carcinoma disease progression [
18].
Bladder cancer is the ninth most common malignancy worldwide, with its highest incidence rates in Western countries [
21]. In Tunisia, bladder cancer is the second cause of cancer in the Tunisian male. The most effective therapy against superficial bladder cancer is intra-vesicle infiltration with Bacillus Calmette Guérin (BCG) [
22]. However, some recurrence and progression occur after this therapy, which renders the response to BCG unpredictable. Hence, it is necessary to pinpoint reliable predictive biomarkers that could identify groups at elevated risk of treatment failure for a specific therapy.
The aim of this study is to assess the prognostic value of three genes in tumors from bladder cancer patients in Tunisia: T-bet, GATA-3 and Bcl-6. We found that upon disease progression, patients with high expression levels of T-bet were related to invasive and high grade of the disease, but were good responders to BCG. In contrast, reductions in Bcl-6 and GATA-3 expression correlated with invasive and high-grade of bladder cancer and were associated with a decrease in disease-free survival. Our results suggest that Th1−, Th2− and Tfh− associated gene expression could represent potential prognostic markers in patients with bladder cancer.