Spatial Immunephenotypes of Distant Metastases but not Matched Primary Urothelial Carcinomas Predict Response to Immune Checkpoint Inhibition

• Published in: European urology 2023-02, Vol.83 (2), p.133-142
• Main Authors: Erlmeier, Franziska, Klümper, Niklas, Landgraf, Laura, Strissel, Pamela L., Strick, Reiner, Sikic, Danijel, Taubert, Helge, Wach, Sven, Geppert, Carol I., Bahlinger, Veronika, Breyer, Johannes, Ritter, Manuel, Bolenz, Christian, Roghmann, Florian, Erben, Philipp, Schwamborn, Kristina, Wirtz, Ralph M., Horn, Thomas, Wullich, Bernd, Hölzel, Michael, Hartmann, Arndt, Gschwend, Jürgen E., Weichert, Wilko, Eckstein, Markus
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen; Carcinoma, Transitional Cell - drug therapy; Humans; Immune Checkpoint Inhibitors - therapeutic use; Immune microenvironment; Immune therapy; Metastatic urothelial cancer; Retrospective Studies; Subtypes; Tumor Microenvironment; Urinary Bladder Neoplasms - drug therapy; Urothelial cancer
• ISSN: 0302-2838; 1873-7560
• DOI: 10.1016/j.eururo.2022.10.020

The tumor immune microenvironment (TIME) is subject to considerable dynamics during metastatic progression. TIME assessment on pretherapeutic biopsied distant metastases shows promising potential for predicting chemotherapy and immunotherapy responses, while TIME assessment in matched primary tumors does not. Thus, it seems reasonable to rely on pretherapeutic metastasis biopsies for biomarker-guided future trials. The value of programmed cell death ligand-1 (PD-L1) to predict durable responses to immune checkpoint inhibitors (ICIs) in metastatic urothelial carcinoma (mUC) is inconsistent. We hypothesize that the use of archived primary tumor material (PRIM) for PD-L1 testing in clinical trials not properly reflecting the metastatic disease status (MET) contributes to this clinical issue. To analyze the predictive and prognostic value of PD-L1, spatial immunephenotypes, and major histocompatibility complex class I (MHC-I) determined in patient-matched PRIM/MET. PD-L1, spatial immunephenotypes, and MHC-I were examined in 154 mUC patients with at least one available pretreatment MET (138 patient-matched PRIM/MET pairs). PD-L1, spatial immunephenotype, and MHC-I status of (patient-matched PRIM and) pretreatment MET were correlated with chemotherapy and ICI response and outcomes. Discordance rates in patient-matched PRIM/MET were 25/30%, 36%, and 49% for PD-L1 (CPS10/IC5%), immunephenotypes, and MHC-I (loss vs preserved), respectively. Correlations with chemotherapy and ICI responses were observed for immunephenotypes and MHC-I status determined in MET (not for PD-L1 alone), but not in PRIM. In case of ICIs, patients with cytotoxic tumor immune microenvironment (TIME) showed durable responses with disease control rates of 90% and a hazard ratio for disease progression/death of 0.05 (95% confidence interval: 0.01–0.65) versus patients with immunedepleted MET (disease control rate 29%). MET MHC-I status added an incremental value to predict durable ICI responses. Limitations include the partly retrospective design and the lack of MET multisampling on individual patient level. The TIME is subject to substantial dynamics during metastatic evolution. MET immunephenotypes and MHC-I statuses show promising potential to predict chemotherapy and durable ICI responses, while the PRIM TIME does not. Thus, future clinical trials should rather rely on pretreatment MET biopsies reflecting the current immunological disease state than on PRIM. Prediction of chemotherapy and r