The CD8 ⁺ /Foxp3 ⁺ ratio, but not the number of OX40 ⁺ TILs, is an independent predictor of tumor recurrence in non-muscle-invasive bladder cancer: a retrospective study

Non-muscle-invasive bladder cancer (NMIBC) frequently recurs and progresses into an aggressive and lethal entity within five years. The clinical management of recurrent tumors remains limited. Therefore, identifying individual patients who are at a high risk of recurrence is crucial for early clinical monitoring and appropriate medical intervention, which may lead to improved outcomes. OX40 is a dual modulator that stimulates effector T cells and suppresses Tregs. It appears to be an ideal molecule for predicting survival outcomes, surpassing the predictive power of single or combined T cell signatures. It has been shown to act as an independent tumor prognostic predictor in various cancers, including non-small cell lung cancer, melanoma, and colorectal cancer. However, its potential as a prognostic tool for tumor recurrence in NMIBC has yet to be investigated. The present study aimed to investigate the potential value of OX40 as a predictor of recurrence risk in patients with NMIBC. Additionally, its downstream effectors, Foxp3 and CD8, were also evaluated. Tissue samples were collected from a cohort of 110 patients diagnosed with NMIBC. Immunohistochemistry was performed to assess the density of stromal OX40⁺, Foxp3⁺, and CD8⁺ tumor infiltrating lymphocytes (TILs). Following survival analysis using the Kaplan-Meier method and log-rank test, we found that tumor recurrence was associated with a decreased density of OX40⁺ and CD8⁺ TILs, an elevated density of Foxp3⁺ TILs, and lower ratios of OX40⁺/Foxp3⁺ and CD8⁺/Foxp3⁺ TILs. However, after adjustment, multivariate COX regression analysis indicated that only the ratio of CD8⁺/Foxp3⁺ was an independent predictor of recurrence risk. The prediction power was assessed by a receiver operating characteristic (ROC) curve analysis. The results demonstrated that the AUC value for the CD8⁺/Foxp3⁺ ratio was better than the other predictive markers. Although the expression of OX40 in TILs was associated with tumor recurrence, our results suggest that the predictive efficacy of a combination of CD8 and Foxp3 was more robust after adjustment. Future research utilizing advanced immunotyping techniques is necessary to validate these findings in larger cohorts.