Clinical Significance of Programmed Death-1 Ligand-1 Expression in Patients with Non-Small Cell Lung Cancer: A 5-year-follow-up Study

Chen, Yanbin; Mu, Chuanyong; Huang, Jianan

doi:10.1177/030089161209800612

Cited by 203 publications

(162 citation statements)

References 42 publications

(42 reference statements)

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“…Previous studies revealed controversy in the prognostic value of PD-L1 for NSCLC. There are some studies suggesting a negative prognostic role (17,(21)(22)(23), while others did not find any prognostic value (24,25). However, other studies reported improved patient outcomes (20,26).…”

Section: Resultsmentioning

confidence: 99%

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

Rashed

Abdelrahman²,

Abdelgawad³

et al. 2017

TJPATH

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IntRoduCtIonLung cancer ranks the first in the incidence and mortality rates amongst all malignancies worldwide. Non-small cell lung cancer (NSCLC) constitutes 80% -85% of all diagnosed cases and more than 70% of NSCLC are diagnosed as an advanced or late disease (1).Recognition of tumor antigens by t cells leads to activation of anti-tumor immune reaction mainly by cytotoxic CD+8 tumor infiltrating lymphocytes (tiLs), but malignant cells may have many pathways to evade the immunological destruction. PD-1 is a co-stimulatory molecule on t-cells that inhibits t cell activation. PD-1, which is a 288-amino acid cell-surface protein, can bind two ligands, PD-L1 and PD-L2, which negatively control the immune response. tumor cells express PD-L1 can inhibit t cell-mediated immune response and can progress to distant metastasis (2,3). CD8 marker is expressed on cytotoxic t cells, natural killer, and dendritic cells. CD8+ t cells are a major component of the cell-mediated immune system against malignant cells. CD8+ t cells undergo differentiation to effector cytotoxic t cells. Then the effector CD8+ cells undergo apoptosis leaving memory cells when a pathogenic response is resolved. Memory t cells and cytotoxic t cells are associated with a more favorable prognosis in NSCLC (4).PD-L1 over-expression has been proved to be a poor prognostic marker in many human cancers (5). PD-1/ PD-L1 interaction suppresses CD8+ tiLs survival and proliferation and leads to apoptosis of tumor-infiltrating lymphocytes. PD-L1 over-expression in tumor cells in a syngeneic transplant model of tumor cells makes them evade from cytotoxic tiLs (6). AbStRACtObjective: Programmed cell death ligand-1 interacts with the immune receptors on the surface of CD8+ tumor infiltrating lymphocytes and PD-1, thereby blocking its anti-tumor activity. therapeutics suppression of this interaction will show a promise in the treatment of non-small cell lung cancer by restoring the functional anti-tumor t-cell activity. We aimed to evaluate the association between the immunohistochemical expression of PD-L1, stromal CD8+ tumor infiltrating lymphocytes and p53 with the clinicopathological characteristics, response to chemotherapy, progression-free-survival, and overall survival. Material and Method:We examined the immunohistochemical expression of PD-L1, stromal CD8+ tiLs, and p53 expression in 50 patients with advanced stage (iii&iV) non-small cell lung cancer.Results: PD-L1 was expressed in 56% of the studied cases. PD-L1 expression was related to unfavorable response to the therapy without significant difference. PD-L1 expression was significantly associated with disease progression, poor progression-free-survival & overall survival. CD8+ tiLs were high in 32% of the cases. tumors with high CD8+ tiLs showed a partial response to therapy and had a better progression-free-survival and overall survival. p53 expressed in 82% of the studied cases. there was a significant negative association between PD-L1 and CD8+ tiLs (p=0.009), while a non-significant association wa...

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Section: Resultsmentioning

confidence: 99%

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

Rashed

Abdelrahman²,

Abdelgawad³

et al. 2017

TJPATH

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show abstract

“…25,[40][41][42] PD-1 and PD-L1 blockade has shown to prolong survival in patients with advanced lung cancer, 17,18,43 indicating that activation of the PD-1/ PD-L pathway inhibits tumor surveillance, thus implicating this pathway as an adverse prognostic factor. However, a recent study demonstrated that PD-L1 (CD274) expression at the protein and mRNA levels was associated with better clinical outcomes in patients with non-small-cell lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Consistent with our results, several reports claimed that elevated PD-L1 expression was predictive of poor clinical outcomes in several cancers including non-small-cell lung cancer. 41,42 Furthermore, upon interaction with PD-1, PD-L1 contributed to an anti-apoptotic effect in tumor cells in a cytosolic domain-dependent manner, 44 indicating that PD-L1 expression in tumor cells might not only induce T-cell exhaustion but also inhibit tumor cell death. In our study, although increased number of CD8 + or PD-1 + tumor-infiltrating lymphocytes were associated with prolonged disease-free survival, a high ratio of PD-1 + /CD8 + tumor-infiltrating lymphocytes was associated with shorter diseasefree survival.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

et al. 2015

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Immunotherapies targeting the programmed cell death-1/programmed cell death-ligand 1 pathway have emerged as promising therapeutic strategies for lung cancer. However, the expression pattern and prognostic implications of programmed cell death-ligand 1 and 2 and programmed cell death-1 in comparison with the histology and genetic alterations in pulmonary adenocarcinomas remains unclear and thus were addressed here. Programmed cell death-ligand 1 and 2 expression in tumor cells and the quantities of programmed cell death-1 + and CD8 + tumor-infiltrating lymphocytes were immunohistochemically evaluated in 497 resected pulmonary adenocarcinomas and analyzed according to clinicopathological and genetic statuses. Programmed cell death-ligand 1 and 2 expression were observed in 59% and 64% of pulmonary adenocarcinomas, respectively, and showed a strong positive correlation with each other (Po 0.001). Programmed cell death-ligand 1 expression was higher in nodal metastasis cases (P = 0.006), smokers (P = 0.056), poorly differentiated tumors and histologic subtypes of solid and micropapillary patterns (Po0.001). There was no significant difference in programmed cell death-ligand 1 and 2 expression according to EGFR mutation status. However, programmed cell death-ligand 1 expression was correlated with ALK translocation (P = 0.054) and expression of EGFR and MET (Po 0.001). Meanwhile, programmed cell death-ligand 2 expression was correlated with ALK translocation (P = 0.052), and expression of MET (Po 0.001) and ERBB2 (P = 0.013). The numbers of CD8 + and programmed cell death-1 + lymphocytes were higher in smokers (P = 0.012 and 0.016) and MET-expressing adenocarcinomas (Po 0.001). Patients expressing programmed cell death-ligand 1 and/or high ratios of programmed cell death-1 + /CD8 + lymphocytes showed shorter disease-free survival (P = 0.001). Our study demonstrated that programmed cell death-ligand 1 and 2 expression varied with histology, EGFR, ALK, MET, and ERBB2 statuses, and activation of the programmed cell death-1/programmed cell death-ligand 1 pathway may be a poor prognostic factor in pulmonary adenocarcinomas.

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“…S3B and S3D; refs. [30][31][32][33][34]. No clinical or pathologic characteristics were associated with PD-L1 expression.…”

Section: Expression Of Pd-l1 and Activation Of Mtor In Human Lung Adementioning

confidence: 97%

Control of PD-L1 Expression by Oncogenic Activation of the AKT–mTOR Pathway in Non–Small Cell Lung Cancer

et al. 2016

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Alterations in EGFR, KRAS, and ALK are oncogenic drivers in lung cancer, but how oncogenic signaling influences immunity in the tumor microenvironment is just beginning to be understood. Immunosuppression likely contributes to lung cancer, because drugs that inhibit immune checkpoints like PD-1 and PD-L1 have clinical benefit. Here, we show that activation of the AKT-mTOR pathway tightly regulates PD-L1 expression in vitro and in vivo. Both oncogenic and IFNg-mediated induction of PD-L1 was dependent on mTOR. In human lung adenocarcinomas and squamous cell carcinomas, membranous expression of PD-L1 was significantly associated with mTOR activation. These data suggest that oncogenic activation of the AKT-mTOR pathway promotes immune escape by driving expression of PD-L1, which was confirmed in syngeneic and genetically engineered mouse models of lung cancer where an mTOR inhibitor combined with a PD-1 antibody decreased tumor growth, increased tumor-infiltrating T cells, and decreased regulatory T cells.

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Clinical Significance of Programmed Death-1 Ligand-1 Expression in Patients with Non-Small Cell Lung Cancer: A 5-year-follow-up Study

Abstract: Up-regulated PD-L1 expression in NSCLC is related to the degree of tumor cell differentiation and TNM stage. PD-L1 status may be a new predictor of prognosis for patients with NSCLC.

Cited by 203 publications

References 42 publications

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

Prognostic significance of programmed cell death ligand 1 (pd-l1), cd8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study

Clinicopathologic analysis of programmed cell death-1 and programmed cell death-ligand 1 and 2 expressions in pulmonary adenocarcinoma: comparison with histology and driver oncogenic alteration status

Control of PD-L1 Expression by Oncogenic Activation of the AKT–mTOR Pathway in Non–Small Cell Lung Cancer

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