Evaluation of PD-L1 and other immune markers in bladder urothelial carcinoma stratified by histologic variants and molecular subtypes

Abstract

Although advanced bladder cancer overall has a poor prognosis, a subset of patients demonstrate durable response to immune checkpoint inhibitors. Evidence shows that the response to checkpoint inhibitors may be associated with type and degree of immune infiltration in the tumor microenvironment. Here, we evaluated immune markers stratified by molecular subtypes and histologic variants. The study utilized a series of urothelial carcinomas (UCs) by tissue microarray, on which histologic variants and molecular subtypes had previously been established. PD1, CD3, CD8 and CD68 expression was evaluated by immunohistochemistry in tumor infiltrating immune cells, while PD-L1 expression in the tumor microenvironment was assessed. Each marker was scored semi-quantitatively (score 0-3). Tumors were clustered by marker scores using agglomerative methods, and associations among markers, histologies, and molecular subtypes were analyzed. PD-L1 expression in the tumor microenvironment significantly correlated with presence of CD3, CD8 and chronic inflammation. Urothelial carcinoma may be classified as either immune high or low based on marker expression. The immune high group is enriched in higher CD3, PD-L1, and genomically-unstable molecular subtype, suggesting it may respond to checkpoint inhibitors. We also identified a degree of intratumoral heterogeneity in immune markers in bladder cancer.

The Immunoscore in Localized Urothelial Carcinoma Treated with Neoadjuvant Chemotherapy: Clinical Significance for Pathologic Responses and Overall Survival

“…We report a difference in immune densities and the Immunoscore between classical UC and variant histologies, which has already been suggested [ 36 , 37 ]. The tumor microenvironment, the Immunoscore, and immune contexture vary according to UC subtypes and variants, and their prognostic and predictive value in these specific settings warrants further assessment [ 38 ].…”

Immune-inflammatory biomarkers as prognostic factors for immunotherapy in pretreated advanced urinary tract cancer patients: an analysis of the Italian SAUL cohort

“…43 Further studies are, therefore, needed to validate the utility of these biomarkers in UC treated with immunotherapy. 44,45 Using tissue microarray analysis, Li et al 46 found that UC could be classified as either immune high or low, with the former subgroup enriched in PD-L1 and with genomically unstable phenotype, which might make it more responsive to ICIs. A recent study has advocated the use of a score, namely the EPSILoN score, which combines three clinical and two inflammatory blood factors (i.e.…”

Indication-specific tumor evolution and its impact on neoantigen targeting and biomarkers for individualized cancer immunotherapies

“…It has long been recognized that levels of CD8+ T cell infiltration and PD-L1 expression within the tumor microenvironment provide important information regarding patient prognosis and likelihood of response to treatment. While thorough investigations into each of these biomarkers across several indications has been done 45, 46 , to our knowledge, analysis of differences across primary and metastatic regions at a single time point has not been performed. We therefore investigated tumor CD8 levels and CD8+ T cell localization as well as PD-L1 tumor and immune cell expression by immunohistochemistry.…”