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

Toru Sakatani,Atsuro Sawada,Shusuke Akamatsu,Kenji Nakamura,Akihiro Hamada,Takayuki Goto,Takashi Kobayashi,Yuki Kita,Hideaki Takada,Takeshi Sano,Masakazu Fujimoto

doi:10.3390/cancers14020263

Abstract

Simple SummaryPembrolizumab, 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 (IFNγ) showed a significant positive correlation with post-progression survival. Finally, we demonstrated that the coincidence of low infiltration of CD8-positive lymphocytes and low IFNγ 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 (IFNγ) 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/IFNγ 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 IFNγ expression was an independent prognostic factor with predictive ability equivalent to previously reported clinical prognosticators.

Highlights

Advanced urothelial carcinoma that is locally advanced, unresectable, or metastatic has a poor prognosis [1]
We demonstrated that high levels of CD8+ tumor-infiltrating lymphocytes (TILs) were significantly associated with a favorable objective response and longer overall survival (OS), while high IFNγ expression in the tumor was significantly correlated with longer Post-progression survival (PPS)
These results suggested that continuation of anti-progressive disease (PD)-1/programmed cell death-ligand 1 (PD-L1) treatment until loss of clinical benefit contributed to favorable PPS

Summary

Introduction

Advanced urothelial carcinoma (aUC) that is locally advanced, unresectable, or metastatic has a poor prognosis [1]. Cisplatin-based chemotherapy has been used mainly as the first-line therapy for aUC over the past several decades with an overall survival (OS) rate of 9–15 months. In aUC patients with resistance to platinum therapy, the median OS is only 5–7 months [2,3]. Over the last several years, results of multiple clinical trials have led the U.S Food and Drug Administration to approve five immune checkpoint inhibitors (ICIs) for aUC [5,6,7]. In the phase 3 KEYNOTE-045 trial using second-line pembrolizumab, the >2-year follow-up period showed an OS of 44.2% and an objective response rate of 21.2% at 24 months [8,9]. Pembrolizumab treatment resulted in serious adverse events in 12% of patients, such as colitis, pneumonitis, and interstitial lung disease. There is an urgent unmet need to develop methods for predicting the treatment efficacy and safety of ICIs for aUC patients

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