T cell subsets, regulatory T, regulatory B cells and proinflammatory cytokine profile in Schistosoma haematobium associated bladder cancer: First report from Upper Egypt

Background The function of different populations of the immune system in bladder cancer (BCa) is well established. However, the cohesive role of the immune cell profile of schistosomal BCa at systemic and tissue levels is still lacking, especially in endemic countries. The balance hypothesized between protumorigenic and antitumor molecules determines the prognosis of tumor progression. This study aimed to investigate the frequency of T cell subsets at both blood and tumor tissue, regulatory T(Treg), regulatory B cells (Breg) and proinflammatory cytokines in S. haematobium-related BCa patients in Egypt. Methodology/Principal findings The frequency of T cell subsets at both blood and tumor tissue, regulatory T(Treg), regulatory B cells (Breg) were studied by flow cytometry and proinflammatory cytokines by ELISA in S. haematobium-related BCa patients in Egypt. The results indicated a significant increase in the activity of T-cell populations, particularly CD3(+), CD4(+), and regulatory T cells (Tregs), and a decrease in cytotoxic CD8(+) T cells in the patient group. An increased proportion of CD19(+)CD24(+)CD38(+) Bregs and proinflammatory cytokines (IL-1 beta, IL-6, and TNF-alpha) was also observed. However, T-cell subpopulations in the tumor microenvironment showed a significant reduction in cancer patients compared to controls. Moreover, positive correlations were observed between the frequencies of Bregs and Tregs, suggesting the promotion of cancer progression besides their relation to the intensity of schistosomal infection. Conclusions/Significance Trapped Schistosoma haematobium eggs in bladder tissue might lead to persistent inflammation that contributes to immunomodulation and promotes tumor progression, as evidenced by the increase in peripheral T helper, Tregs, Bregs and serum tumor-promoting cytokines. Considering the role and integrated functions of specific immune responses in BCa could help future diagnostic and therapeutic implications. Author summary Bladder cancer was found to be associated with S. haematobium infection which is an endemic parasitic infection in many tropical and subtropical areas including Egypt. Toxic products released by Schistosoma eggs serve as antigenic triggers for the immune response. Several studies discussed the function of both resident and recruited immune cell response in BCa as the process of immunoediting in tumor progression is crucial in modulating the clinical course of tumors together with the characteristics of the tumor itself. This study is the first to report the immune cell profile at both epithelial and hematological levels in S. haematobium-related BCa patients in Upper Egypt to explore their immune status. This study would provide evidence of the changes in the proportions of T and B lymphocyte populations in cancer patients relative to the current infection state along with the proinflammatory cytokine profiles of IL-1, IL-6, and TNF-alpha. This study emphasized the role of T helper immune response in schistosomal BCa even under conditions of general immune suppression elicited by cancer and the inhibition of the cytotoxic immune response (CD8(+)) and generation of Tregs (CD4(+)CD25(high)Foxp3), resulting in the suppression of antitumor immunity. Additionally, significant Breg expression in patients seems to be closely linked to increased Treg cell production either peripherally or in the tumor microenvironment (TME), enhancing the conversion of nonactivated CD4(+) cells into Tregs, with a decline in cytotoxic T-cell response in tumor tissue. At the TME, the past chronic inflammation elicited by schistosome egg antigens could be postulated to affect the suppression that occurred in T-cell subsets, thus promoting tumor progression. Also, the profound increase in the serum levels of proinflammatory cytokines correlates with the intensity of schistosomal infection in bladder tissue and suggesting a possible role in malignant transformation.