A Comprehensive Analysis of Immune Response in Patients with Non-Muscle-Invasive Bladder Cancer

SIMPLE SUMMARY: A comprehensive characterization of cell subpopulations involved in the immune response against bladder cancer has not been performed so far. In addition, due to the high prevalence, recurrence and progression capacity of non-muscle-invasive bladder cancer (NMIBC), the identification of novel biomarkers of tumor progression and response to therapy is of utmost importance. The detailed analysis of the immune landscape in these patients is highly relevant to anticipating tumor behavior and optimizing diagnosis methods and tumor management. We present here the results of the first detailed characterization of immune cell populations in the normal bladder, tumor samples and peripheral blood from patients with NMIBC. We have found specific immune cell subsets differentially expressed in these samples and identified potential markers of tumor progression and patient outcome in peripheral blood. These findings provide relevant information about the host immune response against bladder cancer and set the basis for novel non-invasive procedures for patient stratification and monitoring. ABSTRACT: Background. Bladder carcinoma has elevated morbimortality due to its high recurrence and progression in localized disease. A better understanding of the role of the tumor microenvironment in carcinogenesis and response to treatment is needed. Methods. Peripheral blood and samples of urothelial bladder cancer and adjacent healthy urothelial tissue were collected from 41 patients and stratified in low- and high-grade urothelial bladder cancer, excluding muscular infiltration or carcinoma in situ. Mononuclear cells were isolated and labeled for flow cytometry analysis with antibodies aimed at identifying specific subpopulations within T lymphocytes, myeloid cells and NK cells. Results. In peripheral blood and tumor samples, we detected different percentages of CD4+ and CD8+ lymphocytes, monocyte and myeloid-derived suppressor cells, as well as differential expression of activation- and exhaustion-related markers. Conversely, only a significant increase in bladder total monocytes was found when comparing bladder and tumor samples. Interestingly, we identified specific markers differentially expressed in the peripheral blood of patients with different outcomes. Conclusion. The analysis of host immune response in patients with NMIBC may help to identify specific markers that allow optimizing therapy and patient follow-up. Further investigation is needed to establish a strong predictive model.