T cell populations correlate with response and resistance to anti-PD-1 plus lenvatinib combination therapy in hepatocellular carcinoma
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PROVIDER: PRJNA987720 | ENA |
REPOSITORIES: ENA
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Project description:The combination of immune checkpoint blockade and tyrosine kinase inhibitors has shown promising clinical benefits, but the underlying mechanisms driving response and resistance are poorly understood. Here, we performed single-cell RNA- and TCR-sequencing, together with a HBV-peptide-barcoded single-cell RNA-sequencing approach, on paired tumor and blood samples to track the dynamic changes of T cells in HBV+ hepatocellular carcinoma (HCC) patients before or after anti-PD-1 plus lenvatinib combination therapy.
2024-12-17 | GSE235863 | GEO
Project description:Using a kinome-centred CRISPR/Cas9 genetic screen, we identify here that inhibition of the epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer cells. We found that the combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effect in HCC cell lines that express EGFR in vitro and of xenografted HCC cell lines or patient-derived HCC tumours in mice. Herre, we analyzed the different transcriptome profiling of HCC cells treated with DMSO, lenvatinib, gefitinib, and lenvatinib plus gefitinib by RNA-sequencing.
2021-07-22 | GSE157905 | GEO
Project description:Lenvatinib targets multiple oncogenic kinases including vascular endothelial growth factor receptors (VEGFRs) and showed longer median progression-free survival than sorafenib, the only approved treatment for >10 years. With the successful combination therapy of anti-PD-L1 pembrolizumab and anti-VEGF bevacizumab for advanced HCC as well as encouraging experimental findings, lenvatinib was also expected to enhance anti-tumor effects by combining anti-PD-1 pembrolizumab compared to lenvatinib alone; however, the phase III clinical trial failed to show their synergetic survival benefits, highlighting the need for elucidating its mode of action in human HCC specimens after lenvatinib treatment. We performed multi-layer transcriptome analyses of surgically resected human HCC samples after lenvatinib treatment as a neo-adjuvant therapy using RNA-sequencing. Molecular pathway analyses and immunohistochemistry revealed that VEGF-mediated aberrant vascularity and cytotoxic GZMK+CD8 T cells infiltration were significantly improved in lenvatinib-treated HCC; however, the majority of these cytotoxic T cells were trapped in the intratumor fibrotic stroma, suggesting that lenvatinib-treated HCC is in the so-called excluded condition. Excluded tumors are generally believed to be less responsive to immune checkpoint inhibitors, which might be the reason the combination therapy failed to show the additive benefits.
2023-08-08 | GSE223201 | GEO
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer with a dismal prognosis and few effective therapeutic approaches. This study aimed to investigate the efficacy, safety, and predictive biomarkers of hepatic arterial infusion chemotherapy (FOLFOX-HAIC) in combination with lenvatinib and PD-1 inhibitor for patients with advanced iCCA. Locally advanced or metastatic iCCA patients receiving the triple combination therapy of lenvatinib, PD-1 inhibitor, and FOLFOX-HAIC were included in this retrospective study. Primary endpoint was the progression-free survival, evaluated using the RECIST criterion. The secondary endpoints included overall survival, objective response rate, and safety. Whole exome and RNA sequencing of tumor biopsy tissues were performed for biomarker exploration. Between May, 2019 and December 2022, a total of 46 patients were included in this study. The primary endpoint showed a median progression-free survival of 9.40 months (95% CI: 5.28-13.52), with a 6-month progression-free survival rate of 76.1%. The median overall survival was 16.77 months (95% CI, 14.20-19.33), with an objective response rate of 47.8% and disease control rate of 91.3% per RECIST. In addition, 4.3% and 8.7% of patients achieved complete response of all lesions and intrahepatic target lesions per mRECIST, respectively. The most common treatment-related adverse events were neutropenia, thrombocytopenia, elevated aspartate aminotransferase and alanine aminotransferase level. Furthermore, integrated analysis of genetic, transcriptomic, and immunohistochemistry data revealed that pre-existing immunity (high expression level of immune-related signatures and intra-tumoral CD8+ T cell density) in baseline tumour tissues was associated with superior clinical benefits. However, the evaluation of tumor mutation burden did not show potential predictive value in this triple combination. FOLFOX-HAIC in combination with lenvatinib and PD-1 inhibitor demonstrated a promising antitumor activity with manageable safety profiles in patients with advanced iCCA. Moreover, our study also revealed new perspectives on potential biomarkers for clinical efficacy.
2024-02-06 | GSE255058 | GEO
Project description:To investigate the underlying mechanism of the enhanced combination effect of H3B-6527 and Lenvatinib, we conducted RNA-seq analysis of Hep3B cell line xenograft tumors following treatment of tumor bearing mice with one dose of H3B-6527 or Lenvatinib as single agents or in combination. Principal component analysis and hierarchical clustering of differentially expressed genes (differentially expressed genes with adjusted p value < 0.05) showed two largely separated groups in which vehicle and Lenvatinib samples are close to each other whereas the H3B-6527 and the combination samples show similar pattern (Fig. 4A and 4B), suggesting Lenvatinib at 10mg/kg does not drastically alter transcriptional profiles of tumor cells. We then performed pathway enrichment analysis of differentially expressed genes, which showed bile acid metabolism as the top upregulated pathway in H3B-6527 single-agent group, a well-known selective effect to the FGFR4 signaling pathway (Fig. 4C). E2F targets and MYC targets scored as the top downregulated pathways; an effect that is common among many receptor tyrosine kinases including FGFR4. Combination of H3B-6527 and Lenvatinib showed significant upregulation of hypoxia and glycolysis pathways, consistent with anti-angiogenic effect resulting in lack of oxygen and nutrients in tumor microenvironment (Fig. 4C). Moreover, the combination groups showed stronger effects on E2F targets as compared with the single agent groups, and explains the increased antitumor activity observed in efficacy experiments (Fig. 4D). In summary, the RNAseq analysis provided direct mechanistic evidence for the combined anti-angiogenic and anti-tumorigenic effects resulting in enhanced efficacy.
2022-07-13 | GSE198845 | GEO
Project description:Lenvatinib is the FDA-approved targeted drug for advanced hepatocellular carcinoma (HCC), but the efficacy is modest due to drug resistance. Tumor kinome re-wiring governs drug resistance in resistant cancer cells, which is an obstacle for efficient cancer therapy. Therefore, identification the kinases critical for this rewiring process in HCC is crucial.This study reveals the new role of CDK6 and its mechanistic insight in regulation of cancer stemness and drug resistance. These results support the combination treatment of lenvatinib with palbociclib for advanced HCC patients. Further studies will optimize patient target selection and identify the best treatment combinations.
2023-09-29 | PXD038152 | Pride
Project description:To investigate the mechanism of lenvatinib resistance, we established the lenvatinib resistant Huh7 (Huh7 LR) cells by continuous exposuring to lenvatinib (1–20 μM) for approximately 10 months. We then performed gene expression profiling analysis using data obtained from RNA-seq of Huh7 parental (Huh7 P) cells and the lenvatinib resistant Huh7 (Huh7 LR) cells.
2022-08-26 | GSE211850 | GEO
Project description:To understand the role of HIF1a in lenvatinib resistance, we conducted label-free quantitative proteome analysis in both control and lenvatinib resistance cell lines. This analysis revealed changes in the proteome due to the lenvatinib resistance, providing a valuable reference for further investigations.
2024-08-20 | PXD054805 | Pride
Project description:BackgroundLenvatinib combined with programmed cell death protein-1 (PD-1) inhibitors has resulted in good survival outcomes in the treatment of unresectable hepatocellular carcinoma (HCC). Hepatic artery infusion chemotherapy (HAIC) has also attracted attention due to its high response rates and favorable survival for advanced HCC patients. The present study aimed to compare the efficacy of HAIC combined with PD-1 inhibitors plus lenvatinib (HPL) and PD-1 inhibitors plus lenvatinib (PL) in patients with advanced HCC.MethodsBetween July 2018 and December 2019, patients diagnosed with advanced HCC who initially received HPL or PL treatment were reviewed for eligibility. Efficacy was evaluated according to tumor response and survival.ResultsIn total, 70 patients met the criteria and were included in the present study, and they were divided into the HPL group (n = 45) and PL group (n = 25). The overall response rate (40.0 vs. 16.0%, respectively; p = 0.038) and disease control rate (77.6 vs. 44.0%, respectively; p < 0.001) were higher in the HPL group than in the PL group. The median overall survival was 15.9 months in the HPL group and 8.6 months in the PL group (p = 0.0015; HR = 0.6; 95% CI 0.43-0.83). The median progression-free survival was 8.8 months in the HPL group and 5.4 months in the PL group (p = 0.0320; HR = 0.74; 95% CI 0.55-0.98).ConclusionCompared to PL, HPL was associated with a significantly better treatment response and survival benefits for patients with advanced HCC.
| S-EPMC7947809 | biostudies-literature
Project description:In conclusion, we discovered that during combination therapy, tumor tissue demonstrated a more active metabolic reprogramming than normal liver tissue, as indicated by a significant upregulation of CYP1A1 expression. In addition, we validated that CD8T cells secreted more CCL5 after treatment, which upregulated CYP1A1 expression by binding to CCR5, leading to resistance of hepatoma cells to lenvatinib. Finally, we demonstrated that interference with the CCL5/CCR5/CYP1A1 pathway can enhance the efficacy of lenvatinib and combination therapy.
2023-10-30 | GSE246378 | GEO