Clinical Significance of PD-L1 Protein Expression in Surgically Resected Primary Lung Adenocarcinoma

Takada, Kazuki; Okamoto, Tatsuro; Fukushima, Shoji; Shimokawa, Mototsugu; Akamine, Takaki; Takamori, Shinkichi; Katsura, Masakazu; Suzuki, Yuzo; Fujishita, Takatoshi; Toyokawa, Gouji; Morodomi, Yosuke; Okano, Shinji; Oda, Yoshinao; Maehara, Yoshihiko

doi:10.1016/j.jtho.2016.06.006

Cited by 160 publications

(140 citation statements)

References 39 publications

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“…In our study, we also confirmed that papillary, micropapillary, and solid growth patterns are significantly associated with overexpression of PD-L1 compared to lepidic or acinar growth patterns. Besides these clinicopathological characteristics, others have also found that PD-L1 expression is associated with lymphovascular invasion, advanced lymph node stage, or pleural invasion, which we did not observe in our study [24]. …”

Section: Discussioncontrasting

confidence: 90%

The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma

Shi

Sun

et al. 2017

Oncotarget

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BackgroundLung adenocarcinoma (AD) is a common variant of non-small cell lung cancer (NSCLC). Programmed cell death protein 1/programmed cell death ligand 1 (PD1/PD-L1) are promising immunotherapy targets and its expression may be an important biomarker of predicting clinical response. In this study, we evaluated PD-L1 expression in conjunction with clinicopathological characteristics and outcomes in resected lung adenocarcinoma.ResultsThis study included 133 cases of lung adenocarcinoma. PD-L1 expression rate in lung adenocarcinoma was 16.5% at the mRNA level and 13.5% at the protein level, and the kappa coefficient of the two examination methods was 0.824 (P = 0.219, highly correlated). PD-L1 was highly expressed in male patients and smokers with lung adenocarcinoma (P = 0.019 and 0.002, respectively), while no associations were identified between PD-L1 expression and age, tumor size, clinical stage, positive pleural invasion, lymph node metastasis, or therapy methods. Overexpression of PD-L1 was a significant indicator of shorter recurrence free survival time and overall survival (P = 0.000 and 0.000, respectively). Multivariate analysis revealed that PD-L1 expression was an independent risk factor for poor recurrence free survival and overall survival (P = 0.009 and 0.016, respectively).Materials and MethodsExpression of PD-L1 was examined with immunohistochemistry, using the VENTANA PD-L1 (SP263) rabbit monoclonal antibody. mRNA levels of PD-L1 were evaluated using in situ hybridization.ConclusionsPD-L1 overexpression is more frequently observed in male patients and smokers in lung adenocarcinoma. PD-L1 expression is an indicator of worse prognosis in surgically resected lung adenocarcinoma patients.

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Section: Discussioncontrasting

confidence: 90%

The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma

Shi

Sun

et al. 2017

Oncotarget

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“…Previous studies have reported data regarding the association between PD-L1 status and prognosis in cancer, indicating a worse outcome and late stage for patients with high PD-L1 expression [16-20]. Studies have indicated that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, highlighting the need for the evaluation of immune checkpoint inhibiting drugs in this tumour entity [21].…”

Section: Discussionmentioning

confidence: 99%

Membranous and Cytoplasmic Expression of PD-L1 in Ovarian Cancer Cells

Xie

Huang

et al. 2017

Cell Physiol Biochem

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Background: Expression of programmed death-ligand 1 (PD-L1) on tumor cells represents a powerful immune evasion pathway, but the role of intracellular or cytoplasmic PD-L1 has not been investigated in ovarian cancer cells. Methods: Flow cytometry (FCM), Real-time PCR (qPCR), immunohistochemistry (IHC) and western blot were used to determine the expression of PD-L1 in ovarian cancer cells. The cytokines detected in the tumor or tumor associated macrophage (TAM) were used to treat cancer cells. PD-L1 blockade and silencing were used to elucidate the functional significance of cancer-related PD-L1 expression. Results: Based on the results presented, PD-L1 was found variably expressed in the cytoplasm and the cell surface of both HO8910 and SKOV3 cells. TAM or IFN-γ, TNF-α, IL-10 and IL-6 released from TAM stimulated the expression of PD-L1 at the surface of the cancer cells. The IHC results were consistent with the data in vitro showing infiltration of TAM correlated with membranous PD-L1. The increases of PD-L1 at the surface were not due to a shift in the proportion of surface versus intracellular protein, but the contribution of extracellular signal-regulated kinase (ERK)1/2 and phosphoinositide 3-kinase (PI3K) pathway activation. As a consequence, inducible membranous PD-L1 expression on SKOV3 inhibited CD8⁺ T cell function, and cytoplasmic PD-L1 promoted cancer cell growth. Additionally, in mouse models, both PD-L1 and PD-1 mAb resulted in tumor growth inhibition and demonstrated a potential to decrease the number of PD-1⁺CD8⁺T cells. Conclusion: We conclude that TAM induced PD-L1 on the cancer cells represents an immune evasion mechanism. The observations confirm the therapeutic potential of PD-L1/PD-1 mAb to reactivate anti-tumor immunity in ovarian cancer.

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“…The immunohistochemical analysis was conducted using a non-commercial antibody against IL-38 (mouse monoclonal, clone H127C, 0.5 μg/ml, kindly provided by T. Hoshino, Kurume University, Fukuoka, Japan) [26] and a commercial antibody against PD-L1 (rabbit monoclonal, clone SP142, 1:100 dilution, Spring Bioscience, Ventana, Tucson, AZ, USA). Immunohistochemical staining of PD-L1 was performed as described previously [27–29]. For immunohistochemical staining of IL-38, sections were prepared (4 μm thick), dewaxed with xylene, and rehydrated through a graded series of ethanol solutions.…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemical evaluation of PD-L1 was conducted as described previously [29]. Cases with less than 5% tumor membrane staining were considered as negative in this study.…”

Section: Methodsmentioning

confidence: 99%

Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression

et al. 2017

Self Cite

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Interleukin (IL)-38, a novel member of the IL-1 cytokine family, is homologous to IL-1 receptor antagonist (IL-1Ra) and IL-36Ra, and has been reported to act as an antagonist. IL-38 expression is found in tonsil, placenta, and spleen, and recent studies suggest an association between IL-38 and autoimmune diseases. However, whether IL-38 plays a role in carcinogenesis or cancer growth is unclear. In the present study, we identified increases in IL-38 expression by immunohistochemistry in multiple types of cancer cells. In the examination of 417 surgically resected primary lung adenocarcinomas, Fisher’s exact tests showed significant associations between high IL-38 expression and high tumor grades, an advanced T status, advanced N status, advanced stage, and the presence of pleural and vessel invasions. Survival analyses by the Kaplan-Meier method showed that patients with high expression of IL-38 had significantly shorter disease-free survival and shorter overall survival after surgery than patients with low expression of IL-38 (log-rank test: P = 0.0021 and P = 0.0035, respectively). Moreover, programmed cell death-ligand 1 (PD-L1)-positive cases showed higher expression of IL-38 than PD-L1-negative cases (Wilcoxon rank-sum test: P < 0.0001). In conclusion, IL-38 was expressed in tumor cells of various cancers, and IL-38 expression was associated with poor survival of lung adenocarcinoma patients. IL-38 may affect host immunity or the tumor microenvironment, and contribute to the progression of lung adenocarcinoma.

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Clinical Significance of PD-L1 Protein Expression in Surgically Resected Primary Lung Adenocarcinoma

Cited by 160 publications

References 39 publications

The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma

The significance of programmed cell death ligand 1 expression in resected lung adenocarcinoma

Membranous and Cytoplasmic Expression of PD-L1 in Ovarian Cancer Cells

Clinical implications of the novel cytokine IL-38 expressed in lung adenocarcinoma: Possible association with PD-L1 expression

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