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High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict worse survival in human lung adenocarcinoma.

ABSTRACT: Background: Immunotherapy targeting PD-1/PD-L1 represents a breakthrough in the treatment of lung cancer. Pyruvate kinase M2 (PKM2) is not only a critical player in glycolysis, but also conducive to tumor progression and immune response. While both have been linked to lung adenocarcinoma (AC), the correlation and clinical significance of PKM2 and PD-L1 expression in human lung AC tissues remains not entirely explored. Methods: Expression of PKM2 and PD-L1 proteins were detected by immunohistochemistry in 74 lung AC cases and the corresponding noncancerous tissues. Simultaneously, multiplex immunofluorescence was used to detect PKM2, PD-L1, CK, CD3, and CD68 in the lung AC tissues. We measured expression patterns and co-localization of these markers, evaluating their association with clinicopathological features and overall survival. Validation of findings was conducted using mRNA expression data from The Cancer Genome Atlas (TCGA) of 515 lung AC cases. Results: High expression of PKM2 in tumor cells was significantly related with lymph node metastasis and TNM stage (p=0.035, p=0.017, respectively). Moreover, PKM2 expression in tumor cells was positively correlated with tumor PD-L1 expression. High expression of PKM2, PD-L1 in tumor cells and immune cells predicted high mortality rate and poorer survival rates, respectively. Additionally, multivariate Cox regression models indicated that high expression of PKM2 in tumor cells was an independent prognostic factor. Based on TCGA genomic data, high PKM2 mRNA expression was significantly associated with poorer survival (p=0.001). Conclusion: High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict poorer survival rates in patients with lung AC.

SUBMITTER: Long L

PROVIDER: S-EPMC7255362 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict worse survival in human lung adenocarcinoma.

Long Long L Chen Mengxi M Yuan Yu Y Ming Alex Lau AL Guo Wei W Wu Kaisong K Chen Honglei H

Journal of Cancer 20200518 15

<b>Background</b>: Immunotherapy targeting PD-1/PD-L1 represents a breakthrough in the treatment of lung cancer. Pyruvate kinase M2 (PKM2) is not only a critical player in glycolysis, but also conducive to tumor progression and immune response. While both have been linked to lung adenocarcinoma (AC), the correlation and clinical significance of PKM2 and PD-L1 expression in human lung AC tissues remains not entirely explored. <b>Methods</b>: Expression of PKM2 and PD-L1 proteins were detected by ...[more]

PMID: 32489463

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Project description:BackgroundProgrammed cell death protein 1 (PD-1) is a key immune checkpoint that regulates peripheral tolerance and protects against autoimmunity. Programmed death ligand-2 (PD-L2) is a less studied ligand to PD-1 and has yet to be fully explored, especially in pancreatic ductal adenocarcinoma (PDAC).MethodsIn this study, we performed immunohistochemistry to detect the PD-L2, CD3, CD8, transforming growth factor-β2 (TGF-β2) and FOXP3 levels in paraffin sections from 305 patients with resected PDAC as a training set. Expression levels of intratumoral and stromal immune markers were compared in relation to survival using Kaplan-Meier curves, random survival forest model and survival tree analysis. A multivariable Cox proportional-hazards model of associated markers was used to calculate the risk scores.ResultsPD-L2 was expressed in 71.5% of PDAC samples and showed strong correlations with CD3+, CD8+ T cells and FOXP3+ regulatory T cell densities. High levels of intratumoral PD-L2 and FOXP3 were related to poor survival; only stromal FOXP3 overexpression was associated with worse prognosis. Four patterns generated from survival tree analysis demonstrated that PD-L2lowstromalFOXP3low patients had the longest survival, while PD-L2highintratumoralCD3low patients had the shortest survival (P < 0.001). The area under the curve was 0.631(95% confidence interval (CI): 0.447-0.826) for the immune marker-based signature and 0.549 (95% CI: 0.323-0.829; P < 0.001) for the clinical parameter-based signature, which was consistent with the results in the validation set including 150 patients (P < 0.001). A higher risk score indicated shorter survival and could serve as an independent prognostic factor. PD-L2 was also showed associated with TGF-β2 and other immune molecules based on bioinformatics analysis.ConclusionsOur work highlighted PD-L2 as a promising immunotherapeutic target with prognostic value combined with complex tumor infiltrating cells in PDAC.

Project description:Programmed death-ligand 1 (PD-L1) is a crucial negative costimulatory molecule expressed on both tumor and immune cells. It binds to programmed death-1, facilitating tumor escape. Tumor-infiltrating immune cells play a vital role in this process. However, the clinical relationship between PD-L1 expression and tumor-infiltrating immune cells remains uncertain. Immunohistochemistry (IHC) was utilized to assess PD-L1 expression and TIIC markers (CD3, CD4, CD8, CD19, CD31, CD68, CD11c, CD56, and α-smooth muscle actin) in gastric adenocarcinoma tissues from 268 patients. The aim was to explore the prognostic significance of PD-L1 and the infiltration of different immune cell types. The study analyzed overall survival and the correlations between PD-L1 expression, immune cell infiltration, and clinicopathological characteristics. Among the 268 patients, 52 (19.40%) exhibited high PD-L1 expression on tumor cells (TPD-L1), while 167 (62.31%) displayed high PD-L1 expression on immune cells (IPD-L1). Patients with high IPD-L1 expression showed improved survival compared to those with low IPD-L1 expression (P = .028). High TPD-L1 expression associated with various clinicopathological features, such as larger tumor size, poorer differentiation, deeper invasion depth, and higher tumor stage. Conversely, patients with high IPD-L1 expression exhibited shallower tumor invasion and lower mortality rates. Univariate analysis indicated that superficial tumor infiltration, absence of lymph node and distant metastasis, low tumor stage, high IPD-L1 expression, and elevated CD8 and CD19 expression were associated with a reduced risk of tumor progression. Multivariate analysis revealed that patients with high IPD-L1 and CD8 expression or high TPD-L1 and low CD31 expression experienced significantly better overall survival than patients with other combinations. The findings indicate that patients with high PD-L1 expression in immune cells have a substantially improved prognosis. Additionally, the combination of PD-L1 with CD8 or CD31 expression status can serve as an indicator of prognosis in patients with gastric adenocarcinoma.

Dataset Information

High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict worse survival in human lung adenocarcinoma.

Publications

High expression of PKM2 synergizes with PD-L1 in tumor cells and immune cells to predict worse survival in human lung adenocarcinoma.

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