Abstract
Background: The association between the tumor immune microenvironment (TiME) in upper tract urothelial carcinoma (UTUC) and its prognosis remains unclear. We investigated the relationship between TiME and UTUC recurrence patterns. Methods: We evaluated 90 patients who underwent nephroureterectomy for UTUC and divided them into nonrecurrence, distant metastasis, and intravesical recurrence-only groups. We assessed the association of the TiME with clinicopathological factors using surgical tissues and the prognosis of the three groups via multiplex fluorescence immunohistochemistry. Results: The median age was 71 years (44-89), and 58 (64%) were male. Intratumoral CD4+ T cell density was significantly higher in the nonrecurrence group (p = 0.0004) than the other groups, whereas intra- and peritumoral regulatory T cell (Treg; CD3+CD4+FoxP3+ cell) density was higher in the distant metastases group than the intravesical recurrence-only group (p = 0.0025). In the multivariate analysis, pathological T stage and CD4+ T cells, and pathological T stage and Treg were independent predictors of recurrence-free survival (p = 0.045, p = 0.017) and metastatic-free survival (p = 0.027, p = 0.011), respectively. Conclusions: Our study demonstrated that CD4+ T cells and Tregs in the TiME of patients with UTUC were independent predictors of high-risk recurrence together with high pathological stage. The analysis of TiME in surgical specimens may provide an objective indicator of the efficacy of adjuvant therapy in UTUC.