Clinicopathological analysis of PD-L2 expression in colorectal cancer.
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ABSTRACT:
SUBMITTER: Guo PD
PROVIDER: S-EPMC6219115 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Clinicopathological analysis of PD-L2 expression in colorectal cancer.
Guo Peng-Da PD Sun Zhong-Wen ZW Lai Hui-Jun HJ Yang Jie J Wu Ping-Ping PP Guo Yun-Di YD Sun Jing J
OncoTargets and therapy 20181101
<h4>Background</h4>(PD-L2), a ligand of programmed cell death protein 1 (PD-1), is an inhibitory receptor of T cells and activated B cells. Many studies have focused on PD-L1, another ligand of PD-1, and the prognostic significance of PD-L1 has been reported in many tumors. However, the expression of PD-L2 in relation to clinical outcomes has not been fully investigated in cancer patients.<h4>Patients and methods</h4>In this study, we investigated the expression of PD-L2 via immunohistochemistry ...[more]
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Project description:PurposeTo systematically evaluate the correlation between PD-L1 expression and clinicopathological features and prognosis of colorectal cancer (CRC).MethodsSeven databases (PubMed, Cochrane Library, EMBASE, Web of Science, CBM, Wanfang, and CNKI) were searched through May 2020. Risk of bias and quality of evidence were assessed by using the Newcastle-Ottawa scale (NOS), and meta-analysis was carried out by using the Review Manager 5.3 software on the studies with the quality evaluation scores ??6. Meta-regression analysis was used to determine the independent role of PD-L1 expression on CRC prognosis after adjusting clinicopathological features and treatment methods.ResultsA total of 8823 CRC patients in 32 eligible studies. PD-L1 expression was correlated with lymphatic metastasis (yes/no; OR?=?1.24, 95% CI (1.11, 1.38)), diameter of tumor (??5 cm/<?5 cm; OR?=?1.34, 95% CI (1.06, 1.70)), differentiation (high-middle/low; OR?=?0.68, 95% CI (0.53, 0.87)), and vascular invasion (yes/no; OR?=?0.80, 95% CI (0.69, 0.92)). PD-L1 expression shortened the overall survival (hazard ratio (HR) =?1.93, 95% CI (1.66, 2.25)), disease-free survival (HR?=?1.76, 95% CI (1.50, 2.07)), and progression-free survival (HR?=?1.93, 95% CI (1.55, 2.41)). Meta-regression showed that PD-L1 expression played a significant role on poor CRC OS (HR?=?1.95, 95% CI (1.92, 3.98)) and disease-free survival (HR?=?2.14, 95% CI (0.73, 4.52)).ConclusionPD-L1 expression independently predicted a poor prognosis of CRC.
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Project description:Expression of the immune checkpoint ligand CD274 (programmed cell death 1 ligand 1, PD-L1, from gene CD274) contributes to suppression of antitumor T cell-mediated immune response in various tumor types. However, the role of PDCD1LG2 (PD-L2, CD273, from gene PDCD1LG2) in the tumor microenvironment remains unclear. We hypothesized that tumor PDCD1LG2 expression might be inversely associated with lymphocytic reactions to colorectal cancer. We examined tumor PDCD1LG2 expression by IHC in 823 colon and rectal carcinoma cases within two U.S.-nationwide cohort studies and categorized tumors into quartiles according to the percentage of PDCD1LG2-expressing carcinoma cells. We conducted multivariable ordinal logistic regression analysis to assess the associations of tumor PDCD1LG2 expression with Crohn-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, or tumor-infiltrating lymphocytes, controlling for potential confounders, including microsatellite instability, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Tumor PDCD1LG2 expression was inversely associated with Crohn-like lymphoid reaction (Ptrend = 0.0003). For a unit increase in the three-tiered ordinal categories of Crohn-like lymphoid reaction, a multivariable OR in the highest (vs. lowest) quartile of the percentage of PDCD1LG2-expressing tumor cells was 0.38 (95% confidence interval, 0.22-0.67). Tumor PDCD1LG2 expression was not associated with peritumoral lymphocytic reaction, intratumoral periglandular reaction, tumor-infiltrating lymphocytes, or patient survival (Ptrend > 0.13). Thus, tumor PDCD1LG2 expression is inversely associated with Crohn-like lymphoid reaction to colorectal cancer, suggesting a possible role of PDCD1LG2-expressing tumor cells in inhibiting the development of tertiary lymphoid tissues during colorectal carcinogenesis. Cancer Immunol Res; 5(11); 1046-55. ©2017 AACR.
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Project description:Colorectal cancer (CRC) is the second leading cause of cancer death worldwide, and immune checkpoint blockade therapy provides an opportunity for improving the outcome of CRC patients. Recent studies suggest that programmed death ligand-1 (PD-L1) is only expressed in 12% of CRCs. Here, we demonstrate that PD-L2 is expressed in approximately 40% CRCs, and its expression independently associates with poor survival of CRC patients. By detection of PD-L2 expression by immunofluorescence in 124 CRC cases with 10-y survival data, we found significant association between PD-L2 overexpression in cancer cells and worse overall survival (46.3 vs 69.1 mo; p = 0.0004). The association remained significant in multivariate COX regression analysis (hazard ratio = 2.778, 95% confidence interval [CI] = 1.668-4.627; p < 0.0001). In the validation CRC data set, significant association between PD-L2 overexpression and poor survival was supported by the univariate analysis (27.1 vs. 88.9 mo; p = 0.0002) and multivariate model (hazard ratio = 7.09, 95%CI 1.78-28.16; p = 0.005). Western Blot revealed strong induction of PD-L2 expression by interferon-? (IFN?) in CRC cells, and the mRNA levels of both genes were significantly correlated in CRC tissue samples. Suppression of glycosylation with tunicamycin caused a shift in molecular weight and significant decrease in the expression of PD-L2 protein. In conclusion, PD-L2 overexpression in CRC cells, under the regulation by IFN? and glycosylation, associates with poor survival of patients with colorectal cancer. These findings highlight PD-L2 as a promising therapeutic target in CRC and suggest potential routes to control PD-L2 expression in CRC cells.
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Project description:ObjectiveTo analyze the prognostic value of programmed death factor ligand 1 (PD-L1) in colorectal cancer.MethodsElectronic databases, such as PubMed, Web of Science, Embase, and Cochrane library, were searched to identify studies evaluating the PD-L1 expression and overall survival (OS) in these patients. Afterwards, the relevant data were extracted to perform the meta-analysis.ResultsA total of 3481 patients were included in 10 studies. The combined hazard ratio (HR) was 1.22 (95%CI = 1.01-1.48, P = 0.04), indicating that high expression of PD-L1 was significantly correlated with poor prognosis of colorectal cancer. Apropos of clinicopathological features, the merged odds ratio (OR) exhibited that highly expressed PD-L1 was firmly related to lymphatic invasion (OR = 3.49, 95%CI = 1.54-7.90, P = 0.003) and advanced stage (OR = 1.77, 95%CI = 1.41-2.23, P < 0.00001), but not correlative with patients' gender, microsatellite instability, or tumor location.ConclusionThe expression of PD-L1 can be utilized as an independent factor in judging the prognosis of colorectal cancer, and patients with advanced cancer or lymphatic invasion are more likely to express PD-L1. This conclusion may lay a theoretical foundation for the application of PD-1/PD-L1 immunoassay point inhibitors but still needs verifying by sizeable well-designed cohort studies.
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Project description:Evidence is limited regarding the immunologic profile and immune microenvironment of soft tissue sarcoma subtypes. The aim of the present study was to describe the clinical significance and prognostic implications of PD-L1, PD-L2, and PD-1 in patients with retroperitoneal sarcoma (RSar). In this retrospective, multicenter, collaborative study, medical charts were reviewed and the immunohistochemical staining results of resected tissue specimens from 51 patients with RSar were examined. Immunohistochemical staining was performed with primary antibodies against PD-L1, PD-L2, PD-1, and Ki-67. The correlations between the baseline clinical parameters and expression levels of the four molecules in sarcoma cells were evaluated, and their prognostic values after tumor resection were assessed. Dedifferentiated liposarcoma (41%), leiomyosarcoma (20%), and undifferentiated pleomorphic sarcoma (16%) were the three major types identified. Dedifferentiated liposarcoma and leiomyosarcoma showed higher levels of PD-L1 expression than did other sarcomas. The Spearman correlation analysis revealed that baseline serum lactate dehydrogenase levels were moderately and positively correlated with PD-L1 (P=0.02, r=0.41) and PD-L2 (P=0.006, r=0.47) expression. The median recurrence-free and disease-specific survival was 58 and 16 months, respectively, during the 29-month median follow-up after surgery. On univariate analysis, a higher expression level of PD-1 was associated with a higher risk of recurrence, whereas multivariate analyses revealed that independent predictors of recurrence-free and disease-specific survival indicated a high expression of Ki-67 (P=0.03; hazard ratio, 2.29 vs. low expression) and prognostic stage IIIB (P=0.04; hazard ratio, 5.11 vs. stage I-II), respectively. Findings of the current study provide novel insights about the prognostic value of PD-L1, PD-L2, and PD-1 expression in RSar. Serum lactate dehydrogenase levels constitute a potential predictor of PD-L1 and PD-L2 expression levels in RSar. Further investigations are needed to determine the immunologic landscape of RSar and provide a foundation for therapeutic intervention using immune checkpoint inhibitors.
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Project description:BackgroundProgrammed cell death ligand-1 (PD-L1) and ligand-2 (PD-L2) interaction with programmed cell death protein-1 (PD-1) represent an immune-inhibiting checkpoint mediating immune evasion and is, accordingly, an important target for blockade-based immunotherapy in cancer. In non-small-cell lung cancer (NSCLC), improved understanding of PD-1 checkpoint blockade-responsive biology and identification of biomarkers for prediction of a clinical response to immunotherapy is warranted. Thus, in the present study, we systematically described PD-L1 and PD-L2 expression correlated genes in NSCLC.MethodsWe performed comparative retrospective analyses to identify PD-L1 and PD-L2 mRNA expression correlated genes in NSCLC. For this, we examined available datasets from the cancer cell line encyclopedia (CCLE) project lung non-small-cell (Lung_NSC) and the cancer genome atlas (TCGA) projects lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).ResultsAnalysis of the CCLE dataset Lung_NSC identified expression correlation between PD-L1 and PD-L2. Moreover, we identified expression correlation between 489 genes and PD-L1, 191 genes and PD-L2, and 111 genes for both. PD-L1 and PD-L2 also expression correlated in TCGA datasets LUAD and LUSC. In LUAD, we identified expression correlation between 257 genes and PD-L1, 914 genes and PD-L2, and 211 genes for both. In LUSC, we identified expression correlation between 26 genes and PD-L1, 326 genes and PD-L2, and 13 genes for both. Only a few genes expression correlated with PD-L1 and PD-L2 across the CCLE and TCGA datasets. Expression of Interferon signaling-involved genes converged in particular with the expression correlated genes for PD-L1 in Lung_NSC, for PD-L2 in LUSC, and for both PD-L1 and PD-L2 in LUAD. In LUSC, PD-L1, and to a lesser extent PD-L2, expression correlated with chromosome 9p24 localized genes, indicating a chromosome 9p24 topologically associated domain as an important driver of in particular LUSC PD-L1 expression. Expression correlation analyses of the PD-L1 and PD-L2 receptors programmed cell death protein-1 (PD-1), Cluster of differentiation 80 (CD80), and Repulsive guidance molecule B (RGMB) showed that PD-1 and CD80 expression correlated with both PD-L1 and PD-L2 in LUAD. CD80 expression correlated with PD-L2 in LUSC.ConclusionsWe present gene signatures associated with PD-L1 and PD-L2 mRNA expression in NSCLC which could possess importance in relation to understand PD-1 checkpoint blockade-responsive biology and development of gene signature based biomarkers for predicting clinical responses to immunotherapy.
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Project description:Background: Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway are a paradigm-shifting cancer therapy. Programmed cell death ligand 2 (PD-L2) is another ligand of PD-1, but its prognostic significance in solid cancer patients after surgery remains controversial. In this study, we aimed to reveal the prognostic implication of PD-L2 in solid tumors through a meta-analysis. Methods: We searched PubMed, Embase and the Cochrane library for studies reporting the relationship between PD-L2 expression and prognosis or clinicopathological features in solid cancer patients after surgery from inception to January 2018, with language restricted to English. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were determined to explore the prognostic value of PD-L2 expression. Odds ratios (ORs) were also calculated to investigate the relationship between PD-L2 expression and clinicopathological parameters. Results: Sixteen studies incorporating 3,533 patients were included in our meta-analysis. The pooled results revealed that PD-L2 overexpression was a weak negative predictor for overall survival (OS; HR = 1.38, 95% CI = 1.05-1.81, P = 0.021), as well as a strong predictor for poor disease-free survival (DFS)/progression-free survival (PFS) (HR = 1.44, 95% CI = 1.15-1.81, P = 0.001). In subgroup analyses, high PD-L2 expression revealed an unfavorable prognostic prediction for OS in hepatocellular carcinoma (HCC) (HR = 1.60, 95% CI = 1.12-2.29, P = 0.011) and for DFS/PFS in HCC (HR = 1.50, 95%CI = 1.04-2.16, P = 0.031) as well as clear cell renal cell carcinoma (HR = 1.45, 95% CI = 1.03-2.03, P = 0.033). Moreover, PD-L2 expression implied a weak trend toward the presence of lymphatic metastasis (presence vs. absence, OR = 1.61, 95% CI = 0.98-2.65, P = 0.061). Conclusion: High PD-L2 expression may promote tumor metastasis and predict unfavorable prognosis in solid cancer patients after surgery, especially in HCC.
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