Programmed death-ligand 1 expression influenced by tissue sample size. Scoring based on tissue microarrays' and cross-validation with resections, in patients with, stage I–III, non-small cell lung carcinoma of the European Thoracic Oncology Platform Lungscape cohort

Cheney, Richard; Verbeken, Erik; Marchetti, Antonio; Quinn, Anne Marie; Monkhorst, Kim; Stahel, Rolf A.; Rosell, Rafael; Blackhall, Fiona; Dafni, Urania; Kerr, Keith M.; Molina, Miguel Ángel; Bubendorf, Lukas; Weder, Walter; Thunnissen, Erik; Peters, Solange; Finn, Stephen; Hiltbrunner, Anita; Kammler, Roswitha; Geiger, Thomas; Marti, Nesa; Tsourti, Zoi; Polydoropoulou, Varvara; Zygoura, Panagiota; Nicolson, Marianne; Stevenson, David A.; Mathieson, William; Smit, Egbert F.; Radonic, Teodora; Soltermann, Alex; Rulle, Undīne; Curioni, Alessandra; Gray, Steven G.; Gately, Kathy; Barr, Martin P.; Meldgaard, Peter; Madsen, Line Bille; Savic, Spasenija; Lardinois, Didier; Nackaerts, Kristiaan; Dooms, Christophe; Wauters, Els; Borght, Sara Van Der; Biernat, Wojciech; Wrona, Ania; Rzyman, Witold; Jassem, Jacek; Dienemann, Hendrik; Muley, Thomas; Warth, Arne; Luca, Graziano De; Lorito, Alessia Di; Dingemans, Anne-Marie; Speel, Ernst‐Jan M.; Ruland, Andrea; Pokharel, Saraswati; Ferenczy, Philip; Franklin, Lynsey; Baas, Paul; Wiel, B. van de; Camps, Carlos; Martorell, Miguel; Navarro, Atilio

doi:10.1038/s41379-019-0383-9

Cited by 29 publications

(23 citation statements)

References 27 publications

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“…In this study, we evaluated different cores from one tumor to determine heterogeneity between biopsies. The high number of samples with discordant scores for PD-L1 (27%) and PD-L2 (32%) in our study demonstrates their expression heterogeneity in cervical cancer, also shown in other tumor types (56)(57)(58)(59). Core biopsies for patient selection can be punched in a negative area of a (partly) positive tumor, which consequently leads to false-negative results.…”

Section: Discussionmentioning

confidence: 61%

PD-L1 and PD-L2 Expression in Cervical Cancer: Regulation and Biomarker Potential

et al. 2020

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PD-1/PD-L1 immune checkpoint inhibitors show potential for cervical cancer treatment. However, low response rates suggest that patient selection based on PD-L1 protein expression is not optimal. Here, we evaluated different PD-L1 detection methods and studied transcriptional regulation of PD-L1/PD-L2 expression by The Cancer Genome Atlas (TCGA) mRNAseq analysis. First, we determined the copy number of the PD-L1/PD-L2 locus by fluorescence in situ hybridization (FISH), PD-L1 mRNA expression by RNA in situ hybridization (RNAish), and PD-L1/PD-L2 protein expression by immunohistochemistry (IHC) on tissue microarrays containing a cohort of 60 patients. Additionally, distribution of PD-L1/PD-L2 was visualized based on flow cytometry analysis of single-cell suspensions (n = 10). PD-L1/PD-L2 locus amplification was rare (2%). PD-L1 mRNA expression in tumor cells was detected in 56% of cases, while 41% expressed PD-L1 protein. Discordant scores for PD-L1 protein expression on tumor cells between cores from one patient were observed in 27% of cases. Interestingly, with RNAish, PD-L1 heterogeneity was observed in only 11% of the cases. PD-L2 protein expression was found in 53%. PD-L1 mRNA and protein expression on tumor cells were strongly correlated (p < 0.001). PD-L1 and PD-L2 protein expression showed no correlation on tumor cells (p = 0.837), but a strong correlation on cells in stromal fields (p < 0.001). Co-expression of PD-L1 and PD-L2 on macrophage-like populations was also observed with flow cytometry analysis. Both PD-L1 and PD-L2 TCGA transcript levels strongly correlated in the TCGA data, and both PD-L1 and PD-L2 strongly correlated with interferon gamma (IFNG) expression/transcript levels (p < 0.0001). Importantly, patients with high PD-L1/PD-L2/IFNG transcript levels had a survival advantage over patients with high PD-L1/PD-L2 and low IFNG expression. Based on these findings, we conclude that PD-L1/PD-L2 expression in cervical cancer is mainly associated with interferon induction and not gene amplification, which makes FISH unsuitable as biomarker. The heterogeneous PD-L1 and PD-L2 expression patterns suggest IHC unreliable for patient selection. RNAish, in conjunction with interferon signaling evaluation, seems a promising technique for immune checkpoint detection. These results warrant further investigation into their prognostic and predictive potential.

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Section: Discussionmentioning

confidence: 61%

PD-L1 and PD-L2 Expression in Cervical Cancer: Regulation and Biomarker Potential

et al. 2020

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“…Another issue associated with cytology specimens is their small sizes, given that PD-L1 expression is often underscored in small samples. 20,21 Whereas the size of the biopsy was not recorded in the survey, bronchial biopsies are usually approximately 1 mm; thus, combined with cytology specimens, a significant proportion of samples used for PD-L1 IHC are considered small. Awareness of the effect of small sample size on PD-L1 scoring around the 1% threshold is important, emphasizing the need for more or larger biopsies.…”

Section: Discussionmentioning

confidence: 99%

The International Association for the Study of Lung Cancer Global Survey on Programmed Death-Ligand 1 Testing for NSCLC

Mino‐Kenudson

Stang

Daigneault

et al. 2021

Journal of Thoracic Oncology

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“…Nevertheless, PD-L1 amplification might present a useful biomarker that in addition to PD-L1 immunohistochemistry could refine the selection of SqCC patients benefiting from immune checkpoint inhibitor therapy. Also, the issue of tissue heterogeneity would not be as crucial for a stable molecular aberration [33][34][35]. Finally, this genomic change can be easily included in next generation sequencing strategies in the diagnostic routine.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung

Goldmann

Marwitz

Nitschkowski

et al. 2021

Cancer Immunol Immunother

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Gene amplification is considered to be one responsible cause for upregulation of Programmed Death Ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) and to represent a specific molecular subgroup possibly associated with immunotherapy response. Our aim was to analyze the frequency of PD-L1 amplification, its relation to PD-L1 mRNA and protein expression, and to characterize the immune microenvironment of amplified cases. The study was based on two independent NSCLC cohorts, including 354 and 349 cases, respectively. Tissue microarrays were used to evaluate PD-L1 amplification by FISH and PD-L1 protein by immunohistochemistry. Immune infiltrates were characterized immunohistochemically by a panel of immune markers (CD3, CD4, CD8, PD-1, Foxp3, CD20, CD138, CD168, CD45RO, NKp46). Mutational status was determined by targeted sequencing. RNAseq data was available for 197 patients. PD-L1 amplification was detected in 4.5% of all evaluable cases. PD-L1 amplification correlated only weakly with mRNA and protein expression. About 37% of amplified cases were negative for PD-L1 protein. PD-L1 amplification did not show any association with the mutational status. In squamous cell cancer, PD-L1 amplified cases were enriched among patients with high tumoral immune cell infiltration and showed gene expression profiles related to immune exhaustion. In conclusion, PD-L1 amplification correlates with PD-L1 expression in squamous cell cancer and was associated with an immune cell rich tumor phenotype. The correlative findings help to understand the role of PD-L1 amplification as an important immune escape mechanism in NSCLC and suggest the need to further evaluate PD-L1 amplification as predictive biomarker for checkpoint inhibitor therapy.

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Programmed death-ligand 1 expression influenced by tissue sample size. Scoring based on tissue microarrays' and cross-validation with resections, in patients with, stage I–III, non-small cell lung carcinoma of the European Thoracic Oncology Platform Lungscape cohort

Cited by 29 publications

References 27 publications

PD-L1 and PD-L2 Expression in Cervical Cancer: Regulation and Biomarker Potential

PD-L1 and PD-L2 Expression in Cervical Cancer: Regulation and Biomarker Potential

The International Association for the Study of Lung Cancer Global Survey on Programmed Death-Ligand 1 Testing for NSCLC

PD-L1 amplification is associated with an immune cell rich phenotype in squamous cell cancer of the lung

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