ArticleJournal for immunotherapy of cancer2019
Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors.
Article in Journal for immunotherapy of cancer, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed.
- The CCTG PA.7 phase II trial of gemcitabine and nab-paclitaxel with or without durvalumab and tremelimumab as initial therapy in metastatic pancreatic ductal adenocarcinoma.Nature communications · 2022Trial
- Molecular predictors of response to pembrolizumab in thymic carcinoma.Cell reports. Medicine · 2021Trial
- From Tumour to Bloodstream: Advancing PD-L1 Testing With Liquid Biopsies in Non-Small Cell Lung Cancer.Cytopathology : official journal of the British Society for Clinical Cytology · 2026Review
- Biomarker analysis from a Phase 1/1b study of tusamitamab ravtansine in patients with advanced non-small cell lung cancer.Translational oncology · 2026Article
- Interferon Epsilon Loss Is Elusive 9p21 Link to Immune-Cold Tumors, Resistant to Immune Checkpoint Therapy, and Endogenous CXCL9/10 Induction.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2025Review
- RNA sequencing and immunohistochemistry jointly improve tumor biomarker interpretation.Scientific reports · 2025Article
- Programmed Death Ligand 1 (PD-L1) Expression in Lymphomas: State of the Art.International journal of molecular sciences · 2024Review
- A comprehensive single-cell breast tumor atlas defines epithelial and immune heterogeneity and interactions predicting anti-PD-1 therapy response.Cell reports. Medicine · 2024Article
- Plasma cell-free RNA PD-L1 or tissue PD-L1 protein expression and outcomes with first-line immunotherapy in metastatic non-small cell lung cancer.The journal of liquid biopsy · 2024Article
- Evolutionary dynamics of tipifarnib in HRAS mutated head and neck squamous cell carcinoma.Oral oncology · 2024Article
- High CTLA-4 transcriptomic expression correlates with high expression of other checkpoints and with immunotherapy outcome.Therapeutic advances in medical oncology · 2024Article
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- Deciphering transcriptomic determinants of the divergent link between PD-L1 and immunotherapy efficacy.NPJ precision oncology · 2023Article
- Tumor monocyte content predicts immunochemotherapy outcomes in esophageal adenocarcinoma.Cancer cell · 2023Article
- Depiction of neuroendocrine features associated with immunotherapy response using a novel one-class predictor in lung adenocarcinoma.Discover oncology · 2023Article
- Spatial Profile of Tumor Microenvironment in PD-L1-Negative and PD-L1-Positive Triple-Negative Breast Cancer.International journal of molecular sciences · 2023Article
- Construction of ovarian metastasis-related immune signature predicting prognosis of gastric cancer patients.Cancer medicine · 2023Article
- Oncogenic alterations reveal key strategies for precision oncology in melanoma treatment.Annals of translational medicine · 2022Article
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Authors and funding
40 authors.
Funding
Abstract
backgroundPD-L1 immunohistochemistry (IHC) has been traditionally used for predicting clinical responses to immune checkpoint inhibitors (ICIs). However, there are at least 4 different assays and antibodies used for PD-L1 IHC, each developed with a different ICI. We set to test if next generation RNA sequencing (RNA-seq) is a robust method to determine PD-L1 mRNA expression levels and furthermore, efficacy of predicting response to ICIs as compared to routinely used, standardized IHC procedures.
methodsA total of 209 cancer patients treated on-label by FDA-approved ICIs, with evaluable responses were assessed for PD-L1 expression by RNA-seq and IHC, based on tumor proportion score (TPS) and immune cell staining (ICS). A subset of serially diluted cases was evaluated for RNA-seq assay performance across a broad range of PD-L1 expression levels.
resultsAssessment of PD-L1 mRNA levels by RNA-seq demonstrated robust linearity across high and low expression ranges. PD-L1 mRNA levels assessed by RNA-seq and IHC (TPS and ICS) were highly correlated (p < 2e-16). Sub-analyses showed sustained correlation when IHC results were classified as high or low by clinically accepted cut-offs (p < 0.01), and results did not differ by tumor type or anti-PD-L1 antibody used. Overall, a combined positive PD-L1 result (≥1% IHC TPS and high PD-L1 expression by RNA-Seq) was associated with a 2-to-5-fold higher overall response rate (ORR) compared to a double negative result. Standard assessments of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) showed that a PD-L1 positive assessment for melanoma samples by RNA-seq had the lowest sensitivity (25%) but the highest PPV (72.7%). Among the three tumor types analyzed in this study, the only non-overlapping confidence interval for predicting response was for "RNA-seq low vs high" in melanoma.
conclusionsMeasurement of PD-L1 mRNA expression by RNA-seq is comparable to PD-L1 expression by IHC both analytically and clinically in predicting ICI response. RNA-seq has the added advantages of being amenable to standardization and avoidance of interpretation bias. PD-L1 by RNA-seq needs to be validated in future prospective ICI clinical studies across multiple histologies.
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