IFN-Gamma Expression in the Tumor Microenvironment and CD8-Positive Tumor-Infiltrating Lymphocytes as Prognostic Markers in Urothelial Cancer Patients Receiving Pembrolizumab

Simple Summary Pembrolizumab, an immune checkpoint inhibitor, has shown therapeutic benefit for advanced urothelial carcinoma (aUC) patients, but only a limited population achieves a long-term response. Prediction of treatment outcomes for aUC patients receiving immune checkpoint inhibitors is a clinical challenge. We assessed the associations between the expression of multiple immune markers in the tumor microenvironment using immunohistochemistry of tumor tissues obtained from 26 aUC patients who received second-line pembrolizumab treatment. We found that high infiltration of CD8-positive lymphocytes was significantly associated with a favorable objective response and overall and progression-free survival. Furthermore, expression of interferon-gamma (IFN gamma) showed a significant positive correlation with post-progression survival. Finally, we demonstrated that the coincidence of low infiltration of CD8-positive lymphocytes and low IFN gamma expression was an independent prognostic factor for an unfavorable response to pembrolizumab. Although immune checkpoint inhibitors have shown benefit for advanced urothelial carcinoma (aUC) patients, prognostication of treatment efficacy and response duration remains a clinical challenge. We evaluated the expression of immune markers in the tumor microenvironment and assessed their associations with response to and survival after pembrolizumab treatment in 26 aUC patients. High levels of CD8(+) tumor-infiltrating lymphocytes (TILs) were associated with favorable objective responses (23.0% vs. 15.3%, p = 0.0425), progression-free survival (median, 8.8 vs 2.1 months; hazard ratio (HR), 0.24; 95% confidence interval (CI), 0.07-0.66, p = 0.0060), and overall survival (median, >24.0 vs. 5.3 months; HR, 0.17; 95% CI, 0.04-0.56, p = 0.0034) compared with low levels. High interferon-gamma (IFN gamma) expression levels were associated with longer post-progression survival (median, 4.9 vs. 1.0 months; HR, 0.18; 95% CI, 0.04-0.59, p = 0.0027) compared with low expression. Multivariate analysis incorporating clinical prognosticators demonstrated that the coincidence of low CD8(+) T cells/IFN gamma was an independent factor for unfavorable overall survival after pembrolizumab treatment (HR, 4.07; 95% CI, 1.36-12.73; p = 0.0125). The combination of low CD8(+) TILs and IFN gamma expression was an independent prognostic factor with predictive ability equivalent to previously reported clinical prognosticators.

Automated summary

The study investigated the expression of immune markers in the tumor microenvironment of 26 advanced urothelial carcinoma patients receiving Pembrolizumab treatment. High levels of CD8(+) tumor-infiltrating lymphocytes were associated with favorable objective responses, progression-free survival, and overall survival. Additionally, high interferon-gamma (IFN gamma) expression levels were linked to longer post-progression survival. Low infiltration of CD8(+) TILs and low IFN gamma expression were identified as an independent prognostic factor for an unfavorable response to Pembrolizumab.