TY  - JOUR
UR  - http://doi.org/10.3390/cancers13102327
CY  - BASEL
Y1  - 2021///
TI  - Integration of Spatial PD-L1 Expression with the Tumor Immune Microenvironment Outperforms Standard PD-L1 Scoring in Outcome Prediction of Urothelial Cancer Patients
VL  - 13
N2  - Simple Summary Diagnostic PD-L1 assessment of urothelial cancer to predict a patient's immune therapy response remains a matter of controversy. Several contributing factors have been discussed; however, systematic studies are lacking. The present study demonstrates that clinically applied PD-L1 scoring algorithms are influenced by inter-algorithm variability and result in the selection of different "PD-L1" positive populations within the tumor immune microenvironment (TIME). The results further demonstrate that specific immune phenotypes of muscle-invasive urothelial cancer are associated with very different clinical outcomes, which cannot be resolved by PD-L1 testing. Thus, PD-L1 alone not only fails to reflect the TIME, but also has implications for patients. We conclude that a comprehensive integration of PD-L1 expression and immune phenotypes is superior to PD-L1 testing. This might be a novel strategy to predict a patient's response to immune therapy. Background: Immune therapy has gained significant importance in managing urothelial cancer. The value of PD-L1 remains a matter of controversy, thus requiring an in-depth analysis of its biological and clinical relevance. Methods: A total of 193 tumors of muscle-invasive bladder cancer patients (MIBC) were assessed with four PD-L1 assays. PD-L1 scoring results were correlated with data from a comprehensive digital-spatial immune-profiling panel using descriptive statistics, hierarchical clustering and uni-/multivariable survival analyses. Results: PD-L1 scoring algorithms are heterogeneous (agreements from 63.1% to 87.7%), and stems from different constellations of immune and tumor cells (IC/TC). While Ventana IC5% algorithm identifies tumors with high inflammation and favorable baseline prognosis, CPS10 and the TCarea25%/ICarea25% algorithm identify tumors with TC and IC expression. Spatially organized immune phenotypes, which correlate either with high PD-L1 IC expression and favorable prognosis or constitutive PD-L1 TC expression and poor baseline prognosis, cannot be resolved properly by PD-L1 algorithms. PD-L1 negative tumors with relevant immune infiltration can be detected by sTILs scoring on HE slides and digital CD8(+) scoring. Conclusions: Contemporary PD-L1 scoring algorithms are not sufficient to resolve spatially distributed MIBC immune phenotypes and their clinical implications. A more comprehensive view of immune phenotypes along with the integration of spatial PD-L1 expression on IC and TC is necessary in order to stratify patients for ICI.
IS  - 10
ID  - epub56532
KW  - DEATH LIGAND-1; INFILTRATING LYMPHOCYTES; BLADDER-CANCER; SQUAMOUS-CELL; OPEN-LABEL; CARCINOMA; ATEZOLIZUMAB; MULTICENTER; IMMUNOTHERAPY; CHEMOTHERAPY; bladder cancer; urothelial cancer; immune phenotypes; PD-L1; PD-1; TILs
AV  - none
JF  - Cancers
A1  - Weyerer, Veronika
A1  - Strissel, Pamela L.
A1  - Strick, Reiner
A1  - Sikic, Danijel
A1  - Geppert, Carol I.
A1  - Bertz, Simone
A1  - Lange, Fabienne
A1  - Taubert, Helge
A1  - Wach, Sven
A1  - Breyer, Johannes
A1  - Bolenz, Christian
A1  - Erben, Philipp
A1  - Schmitz-Draeger, Bernd J.
A1  - Wullich, Bernd
A1  - Hartmann, Arndt
A1  - Eckstein, Markus
PB  - MDPI
SN  -  2072-6694
ER  -