Dataset Information

Liver kinase B1 in exosomes inhibits immune checkpoint programmed death ligand 1 and metastatic progression of intrahepatic cholangiocarcinoma.

ABSTRACT: The increasing morbidity and high mortality of intrahepatic cholangiocarcinoma (ICC) has led to the urgent need for new diagnostics and therapeutics. Liver kinase B1 (LKB1) exerts a tumor suppressor role in multiple malignances, while its regulatory role in exosomes secreted by ICC cells is obscure. In the present study, exosomes were extracted from cell culture supernatants of RBE and HCCC‑9810 ICC cells as well as plasma of patients with ICC by ultracentrifugation and the morphology of exosomes was identified by transmission electron microscopy. Notably, compared with that of intracellular LKB1, the protein level of exosomal LKB1 was decreased. Silencing intracellular LKB1 increased the protein levels of programmed death ligand 1 (PD‑L1), Slug and phosphorylated‑AKT in exosomes, accompanied by decreased expression levels of exosomal LKB1. Exosomes with lower protein levels of LKB1 promoted the expression of the immune checkpoint PD‑L1, malignant phenotypes of ICC cells in vitro, and cancer metastasis in vivo. Moreover, the low level of exosomal LKB1 in plasma was tightly associated with the poor prognosis of patients with ICC. Collectively, exosomal LKB1 inhibits the immune checkpoint PD‑L1 and metastasis of ICC cells. These findings may provide new methods for the diagnosis and immune therapy of ICC.

SUBMITTER: Liu Z

PROVIDER: S-EPMC9350976 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Liver kinase B1 in exosomes inhibits immune checkpoint programmed death ligand 1 and metastatic progression of intrahepatic cholangiocarcinoma.

Liu Zhuo Z Zhou Kunyan K Zeng Jian J Zhou Xin X Li Huanyu H Peng Ke K Liu Xiang X Li Feng F Jiang Bin B Zhao Ming M Ma Tiexiang T

Oncology reports 20220720 3

The increasing morbidity and high mortality of intrahepatic cholangiocarcinoma (ICC) has led to the urgent need for new diagnostics and therapeutics. Liver kinase B1 (LKB1) exerts a tumor suppressor role in multiple malignances, while its regulatory role in exosomes secreted by ICC cells is obscure. In the present study, exosomes were extracted from cell culture supernatants of RBE and HCCC‑9810 ICC cells as well as plasma of patients with ICC by ultracentrifugation and the morphology of exosome ...[more]

PMID: 35856436

Similar Datasets

Project description:PurposeTo evaluate the expression of programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) in ocular adnexal sebaceous carcinoma (OASC), and to appraise these findings within the context of recent comparable studies.DesignsRetrospective case series.MethodsTwenty cases of primary OASC were immunostained for PD-L1, PD-L2 and CD8. PD-L1 and PD-L2 expression were graded with both the combined positive score (CPS) and the tumor proportion score (TPS). Both raw CPS and TPS were reported, as well as positivity with TPS and CPS ≥1. CD8 expression was graded on a 0-3 scale. Charts were reviewed for clinical correlations. The results of the current study were compared with results of similar recent investigations.ResultsFor the 20 cases, mean expression of PD-L1 with CPS was 29.7 (range 0-101.5) and with TPS was 12.2 (range 0-95.8); mean expression of PD-L2 with CPS was 7.9 (range 0-37.3) and with TPS was 1.9 (range 0-12.9). PD-L1 CPS ≥1 was detected in 95% of OASC, while PD-L1 TPS ≥1 was found in 75%. PD-L2 CPS ≥1 was present in 60%, while only 20% had PD-L2 TPS ≥1. Immune cells appeared to contribute to a substantial proportion of PD-L1 and PD-L2 positivity, and a conspicuous CD8-positive T-lymphocytic infiltrate was present in most tumors. Significant correlations were identified between tissue expression of PD-L1, PD-L2, and CD8. Tissues with greater levels of PD-L1 tended to express higher levels of PD-L2 and CD8. The degree of PD-L1 and PD-L2 expression was also associated with the area in millimeters squared of the immunostained tumor, suggesting that tumor sampling may influence interpretation of PD-L1 and PD-L2 expression in ocular adnexal tumors.ConclusionsThe current and preceding studies confirm that PD-L1 and PD-L2 are expressed in a high percentage of OASCs. These results support the premise that checkpoint inhibitor drugs hold considerable therapeutic promise for patients with OASC and stimulate the institution of clinical trials.

Project description:Introduction: Inhibitors of programmed cell death 1 (PD1) and its ligand (PDL1) have exhibited favorable long-term survival in many types of advanced-stage cancer and current approvals have to date been granted in certain tumour types irrespective of PD-L1 status. Methods: We extracted the following information: study sample size, trial period, cancer types, intervention of treatment, type of PD-L1 antibody, immunohistochemistry (IHC) scoring method, number and percentage of PD-L1 < 1% population, and median follow- up time. PD-L1 expression was defined as percentage of number of PD-L1-stained tumor cells (TPS), area of tumor infiltrated by PD-L1-stained immune cells (IPS), number of PD-L1-stained cells (tumor cells, lymphocytes and macrophages; CPS). Different trials used distinct method to define low PD-L1 expression. The risk of bias of the included trials was assessed by using the Cochrane risk of bias tool for RCTs. Results: Here, a total of 34 trials were included to extract individual patient data (IPD) to evaluate the survival benefit of first line PD1/PDL1 inhibitors vs. standard-of-care (SOC) in patients with PDL1 < 1%. In term of anti-PD-1/PD-L1 monotherapy, OS (HR = 0.90, 0.81-1.01) and PFS (HR = 1.11, 0.97-1.27) between PD-1/PD-L1 inhibitor group and SOC group were comparable. In term of anti-PD-1/PD-L1 combination therapy, PD-1/PD-L1 inhibitor group exhibited longer OS (median 19.5 months vs. 16.3 months; HR = 0.83, 0.79-0.88, p < 0.001) and PFS than those of SOC group (median 8.11 months vs. 6.96 months; HR = 0.82, 0.77-0.87, p < 0.001).Subgroup analysis showed that survival benefit was mainly observed in non-small cell lung cancer (NSCLC) (HROS = 0.74; HRPFS = 0.69; p < 0.001), small-cell lung cancer (SCLC) (HROS = 0.58, p < 0.001; HRPFS = 0.55, p = 0.030), esophageal squamous cell carcinoma (ESCC) (HROS = 0.62, p = 0.005; HRPFS = 0.79, p < 0.001), melanoma (HROS = 0.53, p < 0.001) and nasopharyngeal carcinoma (NPC) (HRPFS = 0.35, p = 0.013). Conclusion: Anti-PD-1/PD-L1 combinational therapy rather than monotherapy exhibit survival benefit in the low PD-L1 population in the first-line setting, and the survival benefit was mainly observed in specific tumor types.

Project description:Necroptosis, a regulated form of necrosis, has emerged as a novel therapeutic strategy that could enhance cancer immunotherapy. However, its role in tumorigenesis is still debated because recent studies have reported both anti- and pro-tumoral effects. Here, we aimed to systematically evaluate the associations between tumor necroptosis (mixed lineage kinase domain-like protein, MLKL; phosphorylated MLKL, pMLKL; and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3, RIPK1-RIPK3 interaction) and tumor-infiltrating immune cells (CD8+ and FOXp3+ T cells and CD163+ M2 macrophages) and tumor PD-L1 by immunohistochemistry in 88 cholangiocarcinoma (CCA) patients who had undergone surgical resection. Their associations with clinicopathological characteristics, survival data, and prognosis were evaluated. MLKL was found to be an unfavorable prognostic factor (p-value = 0.023, HR = 2.070) and was inversely correlated with a clinically favorable immune cell signature (high CD8+/high FOXp3+/low CD163+). Both pMLKL and RIPK1-RIPK3 interaction were detected in CCA primary tissues. In contrast to MLKL, pMLKL status was significantly positively correlated with a favorable immune signature (high CD8+/high FOXp3+/low CD163+) and PD-L1 expression. Patients with high pMLKL-positive staining were significantly associated with an increased abundance of CD8+ T cell intratumoral infiltration (p-value = 0.006). Patients with high pMLKL and PD-L1 expressions had a longer overall survival (OS). The results from in vitro experiments showed that necroptosis activation in an RMCCA-1 human CCA cell line selectively promoted proinflammatory cytokine and chemokine expression. Jurkat T cells stimulated with necroptotic RMCCA-1-derived conditioned medium promoted PD-L1 expression in RMCCA-1. Our findings demonstrated the differential associations of necroptosis activation (pMLKL) and MLKL with a clinically favorable immune signature and survival rates and highlighted a novel therapeutic possibility for combining a necroptosis-based therapeutic approach with immune checkpoint inhibitors for more efficient treatment of CCA patients.

Dataset Information

Liver kinase B1 in exosomes inhibits immune checkpoint programmed death ligand 1 and metastatic progression of intrahepatic cholangiocarcinoma.

Publications

Liver kinase B1 in exosomes inhibits immune checkpoint programmed death ligand 1 and metastatic progression of intrahepatic cholangiocarcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets