Intravesical recurrence is associated with increased Treg and exhausted CD8+ T cells in upper tract urothelial carcinoma.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) includes renal pelvic and ureteral carcinoma, and radical nephroureterectomy (RNU) is the standard surgical treatment for nonmetastatic disease. Despite complete resection, postoperative intravesical recurrence (IVR) occurs in 22% to 47% of patients. It is generally recognized that ureteral tumor exhibits a higher incidence of IVR compared with renal pelvic tumor. However, the immunological mechanisms underlying this difference remain poorly understood. MATERIAL AND METHODS: A total of 26 patients with UTUC without variant histology who underwent laparoscopic RNU at Kyushu University Hospital were classified according to tumor location (Renal pelvic group: n = 15; Ureteral group: n = 11). Clinical characteristics and the spatial distribution of immune cells in UTUC were analyzed and compared between the 2 groups using multiplex immunohistochemistry (mIHC). RESULTS: IVR occurred more frequently in the Ureteral group than in the Renal pelvic group. mIHC analysis revealed significantly higher infiltration of regulatory T (Treg) cells and programmed cell death (PD)-1+ Treg cells in the ureteral group. Furthermore, the infiltration of exhausted CD8+ T cells co-expressing T cell immunoglobulin and ITIM domain (TIGIT) and PD-1 were significantly enriched in the Ureteral group. Across the entire cohort, patients who developed IVR exhibited higher densities of these T-cell subsets compared with those without IVR. CONCLUSIONS: Ureteral tumors demonstrate increased infiltration of Treg cells, PD-1⁺ Treg cells, and TIGIT⁺PD-1⁺CD8⁺ T cells, suggesting an immunosuppressive TME that may contribute to the higher risk of IVR after RNU.