Immune Microenvironment of Muscular-Invasive Urothelial Carcinoma: The Link to Tumor Immune Cycle and Prognosis

In this study, we investigated the relationship between the tumor immune microenvironment (TIME), histological differentiation and hypoxia in patients with muscular-invasive urothelial carcinomas (MIUC) after radical cystectomy. Forty-two cases of pT2-3N0M0 MIUCs underwent clinical, histological and immunohistochemical evaluation by counting CD8+, FOXP3+, CD68+, CD163+ cells and polymorphonuclear leukocytes (PMN) in intra-tumoral and peritumoral areas, assessing PD-L1 and GLUT1 expression for defining the impact of tumor immune contexture on patients' outcomes. Five-year survival rates and overall survival were calculated. Most of the MIUCs demonstrated the immune-desert or immune-excluded TIME, reflecting altered mechanisms of T-cells' activation or traffic into tumors. Tumor immune contexture was closely related to histological differentiation. CD8+ cells were scant in MIUCs with papillary and squamous differentiation, while basal-like or mesenchymal-like histological differentiation was associated with increased density of CD8+ cells. A high rate of PD-L1 expression (47.6%) was not related to immune cell infiltration. M2-macrophages predominated under CD8+ lymphocytes. The abundance of PMN and CD163+ macrophages in MIUCs was associated with high GLUT1 expression. CD8+, CD68+, FOXP3+ cells and PD-L1 status did not affect patients' outcomes, while high CD163+ density and PMN infiltration were associated with the unfavorable outcome of patients with MIUC. These data drive the hypothesis that in MIUC, immune escape mechanisms are shifted towards the role of the innate immunity cells rather than CD8+ lymphocytes' functioning.