Beyond PD-L1 Markers for Lung Cancer Immunotherapy

Wojas‐Krawczyk, Kamila; Kalinka, Ewa; Grenda, Anna; Krawczyk, Paweł; Milanowski, Janusz

doi:10.3390/ijms20081915

Cited by 61 publications

(75 citation statements)

References 81 publications

(147 reference statements)

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“…Recently, a great advancement has been made in immunotherapy, and immune checkpoint inhibitors (ICIs) have been approved as a firstline drug for patients with advanced NSCLC (17). However, programmed death 1 ligand, the most important factor, seemed not like a good indicator to determine whether NSCLC patients were suitable for immunotherapy (18). As a heterogeneous tumor, NSCLC was consistently known as a non-immunogenic tumor.…”

Section: Discussionmentioning

confidence: 99%

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining

Wei

Qin

et al. 2020

Front. Oncol.

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Tumor microenvironment (TME) plays a crucial role in the initiation and progression of lung adenocarcinoma (LUAD); however, there is still a challenge in understanding the dynamic modulation of the immune and stromal components in TME. In the presented study, we applied CIBERSORT and ESTIMATE computational methods to calculate the proportion of tumor-infiltrating immune cell (TIC) and the amount of immune and stromal components in 551 LUAD cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were analyzed by COX regression analysis and protein-protein interaction (PPI) network construction. Then, Bruton tyrosine kinase (BTK) was determined as a predictive factor by the intersection analysis of univariate COX and PPI. Further analysis revealed that BTK expression was negatively correlated with the clinical pathologic characteristics (clinical stage, distant metastasis) and positively correlated with the survival of LUAD patients. Gene Set Enrichment Analysis (GSEA) showed that the genes in the high-expression BTK group were mainly enriched in immune-related activities. In the low-expression BTK group, the genes were enriched in metabolic pathways. CIBERSORT analysis for the proportion of TICs revealed that B-cell memory and CD8+ T cells were positively correlated with BTK expression, suggesting that BTK might be responsible for the preservation of immune-dominant status for TME. Thus, the levels of BTK might be useful for outlining the prognosis of LUAD patients and especially be a clue that the status of TME transition from immune-dominant to metabolic activity, which offered an extra insight for therapeutics of LUAD.

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Section: Discussionmentioning

confidence: 99%

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining

Wei

Qin

et al. 2020

Front. Oncol.

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“…Infiltrating immune cells are an integral component of the tumor immune microenvironment (TIME) and play an important role in increasing the effectiveness of immunotherapy (24). This infiltrating immune cell population is usually a heterogeneous mixture of immune cells, including cell types associated with activity and inhibition (25). Because of the need for different types and subtypes of TIME to be identified in the immunotherapy of tumors, their characteristics and differences must be identified (26).…”

Section: Discussionmentioning

confidence: 99%

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

Zhang

et al. 2020

Oncol Rep

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Establishing a prognostic genetic signature closely related to the tumor immune microenvironment (TIME) to predict clinical outcomes is necessary. Using the Gene Expression Omnibus (GEO) database of a non-small cell lung cancer (NSCLC) cohort and the immune score derived from the Estimation of Stromal and Immune cells in Malignant Tumours using Expression data (ESTIMATE) algorithm, we applied the least absolute shrinkage and selection operator (LASSO) Cox regression model to screen a 10-gene signature among the 448 differentially expressed genes and found that the risk prediction models constructed by 10 genes could be more sensitive to prognosis than TNM (Tumor, Lymph node and Metastasis) stage (P=0.006). The CIBERSORT method was applied to quantify the relative levels of different immune cell types. It was found that the ratio of eosinophils, mast cells (MCs) resting and CD4 T cells memory activated in the low-risk group was higher than that in the high-risk group, and the difference was statistically significant (P= 0.003, P= 0.014 and P= 0.018, respectively). Inconsistently, the ratio of resting natural killer (NK) cells and activated plasma cells in the low-risk group was significantly lower than that in the high-risk group (P= 0.05 and P=0.009, respectively). Kaplan-Meier survival results showed that patients of the high-risk group had significantly shorter overall survival (OS) than those of the low-risk group in the training set (P<0.001). Furthermore, Kaplan-Meier survival showed that patients of the high-risk group had significantly shorter OS than those of the low-risk group (P=0.0025 and P=0.0157, respectively) in the validation set [GSE31210 and TCGA (The Cancer Genome Atlas)]. The 10-gene signature was found to be an independent risk factor for prognosis in univariate and multivariate Cox proportional hazard regression analyses (P<0.001). In addition, it was found that the risk model constructed by the 10-gene signature was related to the clinical related factors in logistic regression analysis. The genetic signature closely related to the immune microenvironment was found to be able to predict differences in the proportion of immune cells (eosinophils, resting MCs, memory activated CD4 T cells, resting NK cells and plasma cells) in the risk model. Our findings suggest that the genetic signature closely related to TIME could predict the prognosis of NSCLC patients, and provide some reference for immunotherapy.

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“…Recent studies have found that changes in plasma cfDNA concentration and bTMB in plasma cfDNA may be used as molecular biomarkers for predicting therapeutic effects in ICI therapy, 29,30 all of which support the exploration of immunotherapy-related molecular biomarkers based on liquid biopsy. 31 In the early study of small samples, it has been found that CTC PD-L1 expression can be detected in peripheral blood of tumor patients. However, previous studies are mostly limited to observation of PD-L1 expression on CTCs, lacking comparison with paired TTs, or the detection method of PD-L1 in TTs is inconsistent with that in CTCs, so it is difficult to judge the actual consistency.…”

Section: Discussionmentioning

confidence: 99%

<p>Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer</p>

Cheng¹,

Wang²,

Lv³

et al. 2020

CMAR

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Background: The expression of programmed cell death ligand 1(PD-L1) is related to the efficacy of immune checkpoint inhibitors on patients with non-small cell lung cancer (NSCLC), but tumor tissue (TT) samples are difficult to obtain, and initial TT samples are difficult to reflect the spatial-temporal heterogeneity. Therefore, we explored the feasibility of separating circulating tumor cells (CTCs) and detecting PD-L1 expression on CTCs. Patients and Methods: Peripheral blood specimens were sampled from 66 NSCLC patients, and CTCs were separated by membrane filtration based on size. For 59 patients with paired TT specimens, the expression of PD-L1 in their CTCs and TTs was determined using the immunohistochemistry and immunocytochemistry based on 28-8 antibody, respectively. The PD-L1 expression in TTs was set as a gold standard for calculation of sensitivity, specificity, consistency, positive predictive value (PPV), and negative predictive value (NPV), and the Cohen kappa coefficient for CTCs and paired TTs was calculated. In addition, the T-test, Chi-square test, and Mann-Whitney U-test were adopted to analyze the correlation of clinical pathological features and prognosis with PD-L1 expression. Results: Sensitivity, specificity, concordance, PPV and NPV of detecting PD-L1 in CTCs of the 41 initial treated patients were 88.89%, 73.91%, 80%, 72.73% and 89.47%, respectively, and the Cohen kappa coefficient of CTC and paired TTs was 0.613. The univariate analysis of survival showed that the progression-free survival time of initial treated patients with positive PD-L1 expression was shorter than that of those with negative PD-L1 expression in CTCs or TTs (P>0.05), and the positive PD-L1 expression in CTCs or TTs had nothing to do with age, sex, smoking status, histological type, and stage (P > 0.05). Conclusion: The study confirms the feasibility of CTC PD-L1 detection in peripheral blood and lays a foundation for exploring real-time and individualized immunotherapy molecular biomarkers.

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Beyond PD-L1 Markers for Lung Cancer Immunotherapy

Cited by 61 publications

References 81 publications

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining

BTK Has Potential to Be a Prognostic Factor for Lung Adenocarcinoma and an Indicator for Tumor Microenvironment Remodeling: A Study Based on TCGA Data Mining

A signature of tumor immune microenvironment genes associated with the prognosis of non‑small cell lung cancer

<p>Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer</p>

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