Gut microbione from Japanease lung cancer cohort
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB36730 | ENA |
REPOSITORIES: ENA
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2023-03-08 | GSE223110 | GEO
Project description:Immunotherapy has improved the prognosis of patients with advanced non-small cell lung
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2023-07-11 | BIOMD0000001074 | BioModels
Project description:Immune checkpoint blockade (ICB), particularly programmed death 1 (PD-1) and its ligand (PD-L1), has shown considerable clinical benefits in patients with various cancers. Many studies show that PD-L1 expression may be biomarkers to help select responders for anti-PD-1 treatment. Therefore, it is necessary to elucidate the molecular mechanisms that control PD-L1 expression. As a potential chemosensitizer and anticancer drug, copper combined with disulfiram (DSF) kills tumor cells by regulating multiple signaling pathways and transcription factors in vitro and in vivo. Here, we showed that DSF increased PD-L1 expression in triple negative breast cancer (TNBC) cells. Through TCGA data analysis, we found that DNMT1 and IRF7 were highly expressed and the hypermethylation states in the IRF7 gene body promoter region in TNBC vs normal breast tissue (NBT). Then, we demonstrated that DSF affected PD-L1 expression via DNMT1-mediated IRF7 hypomethylation in two TNBC cell lines. In vivo experiments, DSF significantly enhanced the response to PD-1 antibody (Ab) in the triple-negative 4T1 BC mouse model. By analyzing the results of the tumor tissue sequencing, the DSF joint anti-PD-1 Ab could be a significant activation of anti-tumor immunity. And the inactive state of immune associated pathways was found to be reversed, such as Th1 and Th2 cell differentiation, antigen processing and presentation, natural killer cell-mediated cytotoxicity and T cell receptor signal transduction. In conclusion, we found that DSF could up-regulate PD-L1 in TNBC cells and elucidated its mechanism. Our findings revealed that the combination of DSF and anti-PD-1 Ab could activate the tumor immune microenvironment (TIME) to show much better antitumor efficacy than monotherapy.
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Project description:Programmed death-ligand 1, PD-L1 (CD274) facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a new mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic-hedgehog (Shh) and TGF- receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBC), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein Caprin-1 to stabilize Shh/TGFBR1/Wnt mRNAs to induce -catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ T regs and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using Sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
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2020-09-24 | GSE158403 | GEO
Project description:New therapeutics targeting immune checkpoint proteins have significantly advanced treatment of non-small cell lung cancer (NSCLC), but protein level quantitation of drug targets presents a critical problem. We used multiplexed, targeted mass spectrometry (MS) to quantify the immunotherapy target proteins PD-1, PD-L1, PD-L2, IDO1, LAG3, TIM-3, VISTA, GITR, and CD40 in formalin-fixed, paraffin-embedded (FFPE) NSCLC specimens. Immunohistochemistry (IHC) and MS measurements for PD-L1 were weakly correlated, but IHC did not distinguish protein abundance differences detected by MS. PD-L2 abundance exceeded PD-L1 in over half the specimens and the drug target proteins all displayed different abundance patterns. mRNA correlated with protein abundance only for PD-1, PD-L1, and IDO1 and tumor mutation burden did not predict abundance of any protein targets. Global proteome analyses identified distinct proteotypes associated with high PD-L1-expressing and high IDO1-expressing NSCLC. MS quantification of multiple drug targets and tissue proteotypes can improve clinical evaluation of immunotherapies for NSCLC.
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