Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC

Bassanelli, Maria; Sioletic, Stefano; Martini, Maurizio; Giacinti, Silvana; Viterbo, Antonella; Anita, Staddon; Liberati, F; Ceribelli, Anna

doi:10.21873/anticanres.12662

Cited by 66 publications

(52 citation statements)

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“…Therefore, strong efforts are currently performed to harmonize the staining of PD-L1 [54]. Next to the analytical variability, PD-L1-specific IHC might not reflect the tumor status due to individuality and tumor heterogeneity [55]. The intra-tumoral heterogeneity is common, varying temporal and in scale and was also present between primary tumors and metastases [56].…”

Section: Altered Pd-l1 Expression In Tumorsmentioning

confidence: 99%

Basis of PD1/PD-L1 Therapies

Seliger

2019

JCM

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It is obvious that tumor cells have developed a number of strategies to escape immune surveillance including an altered expression of various immune checkpoints, such as the programmed death-1 receptor (PD-1) and its ligands PD-L1 and PD-L2. The interaction between PD-1 and PD-L1 results in an activation of self-tolerance pathways in both immune cells as well as tumor cells. Thus, these molecules represent excellent targets for T cell-based immunotherapies. However, the efficacy of therapies using checkpoint inhibitors is variable and only a limited number of patients receive a long-term response, while others develop resistances. Therefore, a better insight into the constitutive expression levels and their control as well as the predictive and prognostic value of PD-1/PD-L1, which are controversially discussed due to the methodological assessment, the dynamic and time-related variable expression of these molecules, is urgently required. In this review, the current knowledge of the PD-L1 and PD-1 genes, their expression in immune and tumor cells, the underlying molecular mechanisms of their regulation and their association with clinical parameters and therapy responses are summarized.

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Section: Altered Pd-l1 Expression In Tumorsmentioning

confidence: 99%

Basis of PD1/PD-L1 Therapies

Seliger

2019

JCM

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“…As the indications for immunotherapies, particularly anti-PD1, are increasing, the need for a reliable biomarker predictive of response has become critical. Tumor PD-L1 expression, used in daily practice, shows limitations in its predictive validity, particularly in consideration of the significant heterogeneity of its expression [31]. Besides, the measurement of tumor mutational burden (TMB) has been recently proposed as a biomarker for immunotherapies in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study

Meyo

Jouinot

Leprieur³

et al. 2020

Cancers

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A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55–109) vs. 658 days (222-not reached); HR: 4.12 (1.95–8.71), p = 0.0002) and OS (HR: 3.99(1.63–9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17–6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive; therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30–0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21–0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.

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“…Clinical studies in various cancer types including melanoma, lung cancer, head and neck cancer and others led to rapid clinical approval of therapeutic antibodies against PD‐1 (programmed cell death protein 1) or PD‐L1 (programmed cell death 1 ligand 1) alone or in combination with CTLA‐4 (cytotoxic T‐lymphocyte‐associated protein 4) inhibitors or conventional chemotherapy over the past few years. Most of these trials employed immunohistochemical (IHC) staining of PD‐L1 on tumor cells and/or immune cells as a predictive biomarker to separate responders from non‐responders, but the discriminatory power of this biomarker has limitations . Searching for additional predictive biomarkers, several subsequent studies, especially in NSCLC, retrospectively employed whole exome or larger gene panel sequencing to determine tumor mutational burden (TMB, e.g.…”

Section: Introductionmentioning

confidence: 99%

Measurement of tumor mutational burden (TMB) in routine molecular diagnostics: in silico and real‐life analysis of three larger gene panels

Endris

Buchhalter

Allgäuer

et al. 2019

Intl Journal of Cancer

103

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Assessment of Tumor Mutational Burden (TMB) for response stratification of cancer patients treated with immune checkpoint inhibitors is emerging as a new biomarker. Commonly defined as the total number of exonic somatic mutations, TMB approximates the amount of neoantigens that potentially are recognized by the immune system. While whole exome sequencing (WES) is an unbiased approach to quantify TMB, implementation in diagnostics is hampered by tissue availability as well as time and cost constrains. Conversely, panel-based targeted sequencing is nowadays widely used in routine molecular diagnostics, but only very limited data are available on its performance for TMB estimation. Here, we evaluated three commercially available larger gene panels with covered genomic regions of 0.39 Megabase pairs (Mbp), 0.53 Mbp and 1.7 Mbp using i) in silico analysis of TCGA (The Cancer Genome Atlas) data and ii) wet-lab sequencing of a total of 92 formalin-fixed and paraffin-embedded (FFPE) cancer samples grouped in three independent cohorts (non-small cell lung cancer, NSCLC; colorectal cancer, CRC; and mixed cancer types) for which matching WES data were available. We observed a strong correlation of the panel data with WES mutation counts especially for the gene panel >1Mbp. Sensitivity and specificity related to TMB cutpoints for checkpoint inhibitor response in NSCLC determined by wet-lab experiments well reflected the in silico data. Additionally, we highlight potential pitfalls in bioinformatics pipelines and provide recommendations for variant filtering. In summary, our study is a valuable data source for researchers working in the field of immuno-oncology as well as for diagnostic laboratories planning TMB testing. What's new?Tumor mutational burden (TMB) is an emerging biomarker to predict response to immune checkpoint inhibitors. While TMB can be measured by whole exome sequencing (WES), costs, turn-around time, and tissue availability currently favor a panel sequencing approach using FFPE tissue for routine diagnostics. However, performance remains to be clarified. Our study is the first worldwide that analyses three major commercial gene panels by comparing TMB approximation across panels as well as against the technical reference standard WES. The data suggest that TMB approximation using gene panel sequencing of FFPE tumor tissue is feasible and can be implemented in routine diagnostics.

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Heterogeneity of PD-L1 Expression and Relationship with Biology of NSCLC

Cited by 66 publications

References 50 publications

Basis of PD1/PD-L1 Therapies

Basis of PD1/PD-L1 Therapies

Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study

Measurement of tumor mutational burden (TMB) in routine molecular diagnostics: in silico and real‐life analysis of three larger gene panels

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