Discordance of PD-L1 Expression at the Protein and RNA Levels in Early Breast Cancer

Abstract

We aimed to assess if the discrepant prognostic information between Programmed Death Ligand 1 (PD-L1) protein versus mRNA expression in early breast cancer (BC) could be attributed to heterogeneity in its expression. PD-L1 protein and mRNA expression in BC tissue microarrays from two clinical patient cohorts were evaluated (105 patients; cohort 1: untreated; cohort 2: neoadjuvant chemotherapy-treated). Immunohistochemistry (IHC) with SP142, SP263 was performed. PD-L1 mRNA was evaluated using bulk gene expression and RNA-FISH RNAscope®, the latter scored in a semi-quantitative manner and combined with immunofluorescence (IF) staining for the simultaneous detection of PD-L1 protein expression. PD-L1 expression was assessed in cores as a whole and in two regions of interest (ROI) from the same core. The cell origin of PD-L1 expression was evaluated using multiplex fluorescent IHC. IHC PD-L1 expression between SP142 and SP263 was concordant in 86.7% of cores (p < 0.001). PD-L1 IF/IHC was weakly correlated with spatial mRNA expression (concordance 54.6–71.2%). PD-L1 was mostly expressed by lymphocytes intra-tumorally, while its stromal expression was mostly observed in macrophages. Our results demonstrate only moderate concordance between the various methods of assessing PD-L1 expression at the protein and mRNA levels, which may be attributed to both analytical performance and spatial heterogeneity.

PD-L1 expression on circulating tumor cells can be a predictive biomarker to PD-1 inhibitors combined with radiotherapy and antiangiogenic therapy in advanced hepatocellular carcinoma

“…In the current studies, the PD-L1 expression could be detected using tissue biopsy and liquid biopsy (circulating tumor cells, CTCs) ( 13 , 16 ). However, because the spatial-temporal heterogeneity of PD-L1 expression is inevitable, the information needed for the selection of appropriate therapy is limited to a single biopsy at a specific point ( 17 – 19 ). CTCs exhibit the advantages of continuous assessment, low invasiveness, and interrogation of the overall tumor burden, rather than a specific area ( 20 , 21 ).…”

PD-L1 mRNA and protein expression in canine mammary carcinomas: Correlation with histopathological grade and molecular markers

“…36 Similar findings of weak concordance between PD-L1 mRNA and protein expression have been reported in previous studies on early human breast cancer. 39 Factors such as post-translational modifications and heterogeneity within tumor tissues may contribute to the lack of correlation between PD-L1 mRNA and protein levels in CMCs.…”

Dissecting Tumor-Immune Microenvironment in Breast Cancer at a Spatial and Multiplex Resolution

“…It was recently demonstrated that different methods yield discrepancies for immune infiltrate assessment [113]. This observation is of utmost importance, since previously non-reproducible results have compromised the potential clinical significance of explored biomarkers [7,8,18]. In this direction, efforts have been undertaken to standardize recommendations for mIHC/IF [38,114] and DSP [115] but several questions still need to be addressed.…”

“…In addition, single biomarker expression demonstrated only modest performance, because of analytical limitations and tumor immune microenvironment (TIME) biology. In the case of the widely studied biomarker, PD-L1, assessment exhibits great inter-observer variability, given the different antibodies, platforms and scoring systems that exist [18]. Besides this, PD-L1 is but one immune checkpoint and interactions within TIME are way more complex [19].…”