Prognostic role of stromal tumor-infiltrating lymphocytes in locally advanced upper tract urothelial carcinoma: A retrospective multicenter study (TSU-02 study)

Locally advanced upper urinary tract urothelial carcinoma (UTUC) exhibits high recurrence and metastasis rates even after radical nephroureterectomy. Adjuvant immunotherapy can be a reasonable option, and a simple, low-cost, and effective biomarker is further needed. Stromal tumor-infiltrating lymphocytes (sTILs) has been demonstrated as a prognostic and predictive biomarker in various tumor types, but not yet in locally advanced UTUC. In this multicenter, real-world and retrospective study, we tried to investigate the prognostic role of sTIL and its correlation with the PD-L1/PD-1/CD8 axis by reviewing the clinicopathologic variables of 398 locally advanced UTUC patients at four high-volume Chinese medical centers. sTIL density was evaluated with standardized methodology on H&E sections, and patients were stratified by the cutoff of sTIL (50%). Results showed that high sTIL indicated improved survival (CSS, p = .022; RFS, p = .015; DFS, p = .004), and was an independent predictor of better CSS (HR, 0.577; 95% CI, 0.391-0.851; p = .006), RFS (HR, 0.613; 95% CI 0.406-0.925; p = .020) and DFS (HR, 0.609; 95% CI, 0.447-0.829; p = .002). A strongly positive correlation between sTIL density and the expression level of PD-1/PD-L1/CD8 axis was observed. We also found that aristolochic acid (AA) exposure was associated with increased sTIL and elevated PD-L1 expression, indicating that AA-related UTUC might be a distinct subgroup with unique tumor microenvironment characteristics. Our results show that sTIL can be an easily acquired biomarker for prognostic stratification in locally advanced UTUC.