Myricetin inhibits interferon-γ-induced PD-L1 and IDO1 expression in lung cancer cells.

Programmed death ligand-1 (PD-L1) and indoleamine 2, 3-dioxygenase 1 (IDO1) are immune checkpoints induced by interferon-γ (IFN-γ) in the tumor microenvironment, leading to immune escape of tumors. Myricetin (MY) is a flavonoid distributed in many edible and medicinal plants. In this study, MY was identified to inhibit IFN-γ-induced PD-L1 expression in human lung cancer cells. It also reduced the expression of IDO1 and the production of kynurenine which is the product catalyzed by IDO1, while didn't show obvious effect on the expression of major histocompatibility complex-I (MHC-I), a crucial molecule for antigen presentation. In addition, the function of T cells was evaluated using a co-culture system consist of lung cancer cells and the Jurkat-PD-1 T cell line overexpressing PD-1. MY restored the survival, proliferation, CD69 expression and interleukin-2 (IL-2) secretion of Jurkat-PD-1 T cells suppressed by IFN-γ-treated lung cancer cells. Mechanistically, IFN-γ up-regulated PD-L1 and IDO1 at the transcriptional level through the JAK-STAT-IRF1 axis, which was targeted and inhibited by MY. Together, our research revealed a new mechanism of MY mediated anti-tumor activity and highlighted the potential implications of MY in tumor immunotherapy.

Successful Treatment of Advanced Intrahepatic Cholangiocarcinoma With a High Tumor Mutational Burden and PD-L1 Expression by PD-1 Blockade Combined With Tyrosine Kinase Inhibitors: A Case Report.

Advanced intrahepatic cholangiocarcinoma (iCCA) is not suitable for surgical treatment. Guided by the concept of precision medicine, preoperative systematic treatment may reshape the clinical outcomes of advanced intrahepatic cholangiocarcinoma patients. We describe the case of a 38-year-old female who has been diagnosed with stage IV intrahepatic cholangiocarcinoma with a high tumor mutational burden and positively programmed death-ligand 1 (PD-L1) expression. The patient was treated with programmed cell death 1 (PD-1) inhibitors combined with tyrosine kinase inhibitors (TKIs). After 7 cycles of combination therapy, she underwent radical resection and no tumor cells were found in the postoperative histopathological examination. In addition, the patient's survival time had reached 25 months, as of August 2021. To date, this is the first case of successful radical resection after combined immunotherapy with TKIs for advanced PD-L1-positive intrahepatic cholangiocarcinoma with a high tumor mutational burden (TMB). The case provides a new approach to the treatment of advanced intrahepatic cholangiocarcinoma.

PD-L1 and VEGFR-2 expression in synchronous metastatic renal cell carcinoma treated with targeted therapy following cytoreductive nephrectomy.

OBJECTIVES: Few studies have independently investigated the population of patients with synchronous metastatic renal cell carcinoma (smRCC). In this study, we evaluated programmed death protein-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR-2) expression in primary tumor tissue of smRCC. METHODS: A total of 96 patients with smRCC who were treated with cytoreductive nephrectomy followed by targeted therapy from January 2006 to January 2013 were identified. PD-L1 and VEGFR-2 expression were evaluated by immunohistochemistry. Kaplan-Meier and Cox methods were used for analysis. RESULTS: PD-L1 and VEGFR-2 protein immunopositivity were observed in 39.6% (38 of 96) and 58.3% (56 of 96) of patients, respectively. A significant correlation was detected between VEGFR-2 and PD-L1 expression (P = 0.030). Based on PD-L1 and VEGFR-2 expression, patients with intermediate-risk disease (n = 63) were divided into 4 subgroups including patients who were PD-L1 (+) VEGFR-2 (+) (n = 21), PD-L1 (+) VEGFR-2 (-) (n = 11), PD-L1 (-) VEGFR-2 (+) (n = 15) and PD-L1 (-) VEGFR-2 (-) (n = 16). Compared to the PD-L1 (-) VEGFR-2 (+), PD-L1 (+) VEGFR-2 (+) and PD-L1 (-) VEGFR-2 (-) groups, patients in the PD-L1 (+) VEGFR-2 (-) group had shorter progression-free survival (median, 9.0 vs. 20.0, 16.0 and 15.5 months, P < 0.05) and overall survival (median, 14.0 vs. 33.0, 24.0 and 26.5 months, P < 0.05). CONCLUSIONS: Intermediate-risk smRCC patients with PD-L1-positive and VEGFR-2-negative expression who were treated with targeted therapy following cytoreductive nephrectomy had poor prognoses. We suggest that other treatments beyond sunitinib or sorafenib may be explored in this subgroup.

ß-elemene suppresses the malignant behavior of esophageal cancer cells by regulating the phosphorylation of AKT.

BACKGROUND: Esophageal cancer is a digestive tract malignancy, ranking sixth among the world's deadliest tumor incidence. However, the pathogenesis of esophageal cancer is complex and the prognosis remains poor. Therefore, in-depth study of the pathogenesis and developing effective treatments are of great value for esophageal cancer. ß-elemene is a natural monomeric compound derived from the Chinese herbal Curcuma wenyujin. ß-elemene has been reported to have anti-tumor effects and used as an adjunct to clinical therapy for multiple cancers. This study aims to explore the effects of ß-elemene on esophageal cancer and its related molecular mechanisms. METHODS: TE-1 and KYSE-150 cells were used to evaluate the activity of ß-elemene on esophageal cancerin vitro and in vivo. Western blot was performed for protein expression assessment. CCK8 assay and cell cycle analysis were used for proliferation testing. Flow cytometry was performed for apoptosis detection. Wound healing assay was subjected to assess the migration ability. Transwell chamber assay was applied to assess the invasion ability. HE staining, TUNEL staining and immunohistochemical staining were used to evaluate the changes in tumor tissues. RESULTS: We found that ß-elemene treatment suppressed proliferation, as well as induced apoptosis of esophageal cancer cells. In addition, ß-elemene inhibited the migration and invasion ability of esophageal cancer cells. Furthermore, ß-elemene exerted its effects against esophageal cancer by specifically regulating AKT signaling, thereby controlling the expression of PD-L1. CONCLUSION: ß-elemene inhibits proliferation and metastasis of esophageal cancer cells by regulating the phosphorylation of AKT.

The PD-1/PD-Ls pathway is up-regulated during the suppression of experimental autoimmune encephalomyelitis treated by Astragalus polysaccharides.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of CNS. Astragalus polysaccharides (APS), the main active extract from astragalus membranaceus which is a kind of traditional Chinese medicinal herb, is associated with a variety of immunomodulatory activities. We have evaluated the therapeutic effects of APS in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). It was found that APS could effectively alleviate EAE through inhibiting MOG35-55-specific T cell proliferation and reducing the expression of proinflammatory cytokines, which is mediated by up-regulating the expression of PD-1/PD-Ls signaling pathway. Our results demonstrated that EAE could be suppressed significantly by APS administration. It indicated that APS might be a potential of developing innovative drug for the therapy of MS.

Association of PD-L1 Expression with Tumor-Infiltrating Immune Cells and Mutation Burden in High-Grade Neuroendocrine Carcinoma of the Lung.

INTRODUCTION: The immune microenvironment of high-grade neuroendocrine carcinoma of the lung, including programmed death ligand 1 (PD-L1) expression, has not been well characterized. METHODS: On the basis of immunohistochemistry (IHC) results, PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) was scored as follows: TC0 and IC0 were defined as PD-L1 expression less than 1%, TC1 and IC1 as at least 1% but less than 10%, TC2 and IC2 as 10% or more but less than 50%, and TC3 and IC3 as 50% or more. Phosphatase and tensin homolog (PTEN) IHC was scored as either lost or retained expression. The Ion AmpliSeq Comprehensive Cancer Panel (ThermoFisher Scientific, Waltham, MA) was used to identify mutations in all coding exons of 409 cancer-related genes. RESULTS: A total of 192 patients with large cell neuroendocrine carcinoma (LCNEC) (n = 72) and SCLC (n = 120) were studied. The prevalence of PD-L1 expression on TCs was 15.1% (29 of 192). IC infiltration and PD-L1 expression on ICs were observed in 34.4% of patients (66 of 192) and 31.3% of patients (60 of 192), respectively. The prevalence of IC infiltration and PD-L1 expression on IC were more strongly correlated with LCNEC than with SCLC (57.6% versus 23.3%, p < 0.01; 45.8% versus 22.5%, p < 0.01) and high nonsynonymous mutations (p = 0.05 and .04). PTEN loss was found in 9.5% of patients (18 of 189) and showed no correlation with PD-L1 expression. Progression-free survival was better in patients with IC infiltration than in those without IC infiltration (median 11.3 versus 6.8 months [p < 0.01]) and in patients with PD-L1 expression of IC1/2/3 than in those with expression of IC0 (median 11.3 versus 7.0 months [p = 0.03]). CONCLUSION: These findings suggest that the PD-1/PD-L1 pathway is activated in the microenvironment of pulmonary high-grade neuroendocrine carcinoma and correlated with a higher mutation burden.