The association between PD-L1 and EGFR status and the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs

Tang, Yanna; Fang, Wenfeng; Zhang, Yaxiong; Hong, Shaodong; Kang, Shiyang; Yan, Ye; Chen, Nan; Zhan, Jie; He, Xiaobo; Qin, Tao; Li, Ge; Tang, Wenyi; Peng, Peijian; Zhang, Li

doi:10.18632/oncotarget.3694

Cited by 205 publications

(195 citation statements)

References 37 publications

(43 reference statements)

Supporting

Mentioning

174

Contrasting

Order By: Relevance

“…Increased expression of PD-L1 is significantly associated with poor prognosis in many cancers. Specifically in human NSCLC, it has been associated with tumor aggressiveness and postoperative recurrence [32]. One study demonstrated that increased expression of PD-L1 in lung cancer may contribute to escape of tumor cells from the immune response by suppressing maturation of tumor-infiltrating dendritic cells [33].…”

Section: Discussionmentioning

confidence: 99%

MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC

Xie

Liang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Programmed death ligand1(PD-L1) plays a role in the development and progression of non-small cell lung cancer (NSCLC). This study aimed to identify miRNA(s) that are responsible for regulation of expression of PD-L1 in NSCLC, and to investigate the role of PD-L1 in regulation of the cell cycle in NSCLC. Methods: We predicted the target miRNA of PD-L1, which was miR-140, using the online tools TargetScan and miBase. In NSCLC cells obtained from clinical specimens, in addition to A549 and NCI-H1650 cell cultures, western blots were used to detect the level of expression of proteins, while real-time PCR was used to determine the level of expression of PD-L1, miR-140, cyclin E, and β-actin. Transfection with miR-140 mimics, miR-140 inhibitors, and PD-L1 siRNA were conducted using commercial kits. To determine whether miR-140 directly binds PD-L1, a luciferase reporter gene with wild type or mutated PD-L1 was used. Cell viability was measured with the MTT assay, and PI staining was used for cell cycle analysis. Results: We found low expression of miR-140 and high expression of PD-L1 and cyclin E in NSCLC cells. Over-expression of miR-140 suppressed the expression of PD-L1 by directly binding its 3’ UTR, and was also associated with decreased expression of cyclin E and inhibition of cellular proliferation in A549 and NCI-H1650 cells. Inhibition of PD-L1, in the absence of manipulations to miR-140, also decreased the expression of cyclin E. Conclusion: We conclude that miR-140 directly suppresses PD-L1 and inhibits the miR-140/PD-L1/cyclin E pathway in NSCLC.

show abstract

Section: Discussionmentioning

confidence: 99%

MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC

Xie

Liang

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…23 To account for this, we used a commercially available, anti-PD-L1 antibody that has been independently validated. [24][25][26] We also evaluated PD-L1 expression using cut-offs that have been associated with beneficial response to PD-1/PD-L1 inhibitors in clinical studies. 7,27 Another issue associated with the analysis is the use of tissue microarrays, in which heterogeneous staining of tumors is difficult to evaluate.…”

Section: Pd-l1 Expression In Colorectal Cancermentioning

confidence: 99%

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

et al. 2016

View full text Add to dashboard Cite

Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape (adaptive immune resistance), and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression. We performed immunohistochemistry for PD-L1 on 181 cases of colorectal carcinoma with known microsatellite instability and mutational status, and correlated PD-L1 expression with clinicopathologic features including tumor-infiltrating lymphocyte burden/immunophenotype, tumor mutational profile, and disease-specific survival. PD-L1 was expressed in tumors from 16 patients (9%) who were more often older (P = 0.006) and female (P = 0.035), with tumors exhibiting a larger size (P = 0.013), but lower stage (Po0.001). PD-L1 expression was associated with increased CD8 and TBET-positive tumor-infiltrating lymphocytes, medullary phenotype, poor differentiation, microsatellite instability, BRAF mutation (Po 0.001 for each), and a lower frequency of KRAS mutation (P = 0.012). On multivariate analysis, PD-L1 expression was associated with medullary morphology and frequent CD8-positive tumor-infiltrating lymphocytes, suggesting adaptive immune resistance. PD-L1 positivity was not predictive of survival in the entire cohort, but it was associated with a lower disease-specific survival within the microsatellite-instability high cohort. PD-L1 expression in colorectal carcinoma is associated with clinicopathologic and molecular features of the serrated pathway of colorectal carcinogenesis, and is associated with a worse outcome within microsatellite-unstable tumors. These findings support the role of PD-L1 expression in providing normally immunogenic colorectal carcinoma a means of immune evasion and a more aggressive biology, provide a potential mechanistic explanation for the favorable response of microsatellite-unstable colorectal carcinoma to PD-1/PD-L1 pathway blockade, and suggest potential predictive and prognostic roles of PD-L1 immunohistochemistry in colorectal carcinoma.

show abstract

“…Another retrospective study of 56 patients with EGFR-mutant advanced lung adenocarcinoma demonstrated a significantly higher diseasecontrol rate (p=0.004), longer pFs (p=0.001), and os (p=0.004) after TKi therapy in pD-L1-positive patients (44). A third retrospective analysis of 170 patients with advanced NscLc treated with EGFR-TKis indicated that pD-L1 expression was associated with significantly shorter os in patients with wild-type EGFR (p=0.029), but not in those with mutant EGFR (p=0.932) (45). combination therapy of pD-L1 blockade and EGFR-TKis was investigated in an escalation phase i study where durvalumab was utilized along with gefitinib in two cohorts (cohort A: MEDi4736 at 3 mg/kg every 2 weeks and cohort B at 10 mg/kg every 2 weeks).…”

Section: Combination With Targeted Therapymentioning

confidence: 99%

Immune-based Therapies for Non-small Cell Lung Cancer

Rafei

El-Bahesh

Finianos³

et al. 2017

View full text Add to dashboard Cite

Lung cancer is the leading cause of cancer-related death in males, and the second leading cause of death in females worldwide (1). Non-small cell lung cancer (NscLc) accounts for 85% to 90% of all lung cancer. There are different subtypes of NscLc that are grouped together because, until recently, the approach to treatment as well as prognosis was often similar. These subtypes are squamous cell carcinoma (sqNscLc), adenocarcinoma, large cell carcinoma and more poorly differentiated variants (2). squamous cell carcinoma constitutes about 25-30% of all lung cancer. it originates from the bronchial lining, and is often linked to a history of smoking. Adenocarcinoma represents around 40% of lung cancer. it emerges from mucus-secreting cells. While this type of cancer occurs mainly in current and former smokers, it is the most common type of lung cancer occurring in non-smokers. Large-cell carcinoma accounts for about 10% to 15% of lung cancer and tends to grow and spread quickly (1).Treatment options for NscLc have evolved tremendously over the past 15 years, especially with the advent of genetic and molecular techniques to characterize the driver mutations at the cellular level. overall survival (os) rates from lung cancer have been increasing slowly over the past decade for both men and women. This is mainly due to reduction in smoking over the past 50 years, although the decline in the rates of lung cancer in men started significantly before that in women (3). several treatment modalities are being used including surgery, radiation therapy, chemotherapy, targeted therapy, laser therapy, photodynamic therapy, radiofrequency ablation, cryosurgery, electrocautery, and watchful waiting. New modalities are being tested in clinical trials and they include immunotherapy, combination therapies and chemoprevention (4). To date, there are no studies that evaluate the best sequence of available therapies, and as such, the choice of therapy is highly personalized and likely depends on the setting in which available drugs were investigated, stage of disease, cytogenetic or molecular profile, performance status, toxicities, and medical comorbidities.For a long time, lung cancer has been considered to be non-immunogenic. However, after the success of immunotherapies in melanoma (5), there has been great interest and investigation in the immune checkpoint inhibitors in NscLc. These immune inhibitors have shown promising results in front-line therapy and after failure of multiple lines, as well as in monotherapy and combination 377Τhis article is freely accessible online.Correspondence to: imad Tabbara, MD,

show abstract

The association between PD-L1 and EGFR status and the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs

Cited by 205 publications

References 37 publications

MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC

MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC

PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes

Immune-based Therapies for Non-small Cell Lung Cancer

Contact Info

Product

Resources

About