Ontology highlight
ABSTRACT:
PROVIDER: PRJNA974502 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24677353.fastq.gz | Fastqsanger.gz | |||
| SRR24677353_1.fastq.gz | Fastqsanger.gz | |||
| SRR24677353_2.fastq.gz | Fastqsanger.gz | |||
| SRR24677354.fastq.gz | Fastqsanger.gz | |||
| SRR24677354_1.fastq.gz | Fastqsanger.gz |
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Project description:ACSL4-programmed sphingomyelin metabolism rejuvenates tumor-infiltrating T-cells to enhance the efficacy of anti-PD-1 immunotherapy
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Project description:<p>Background: The objective response rate of anti-programmed death receptor 1 (PD-1) immunotherapy in hepatocellular carcinoma (HCC) remains limited. The tumor immunosuppressive microenvironment mediated by regulatory T cells (Tregs) is a key bottleneck. The traditional Chinese medicine (TCM) compound Fuzheng Jiedu Xiaoji Formula (FZJDXJ) has been proven to improve the clinical efficacy of adjuvant therapy for HCC and remodel the tumor immunosuppressive microenvironment, yet its sensitizing effect and underlying mechanism on PD-1 inhibitors remain unclear.</p><p>Methods: A total of 55 clinical patients were enrolled, who received either immunotherapy alone or FZJDXJ combined with immunotherapy for 3 cycles. The 1-year efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and peripheral immune responses were analyzed by multicolor flow cytometry. A Hepa1-6 orthotopic HCC mouse model was established and divided into four groups: model group, anti-PD-1 monotherapy group, FZJDXJ monotherapy group, and FZJDXJ combined with anti-PD-1 group. Tumor growth, as well as the function of Tregs and CD8+T cells in the periphery and tumor infiltrates, were assessed. Transcriptomic and metabolomic analyses were conducted to explore the molecular mechanisms and metabolic characteristics of the tumor microenvironment, with in vitro for validation.</p><p>Results: In the clinical cohort, the 1-year disease control rate (DCR) of the combination therapy group was significantly increased by 28.5% (83.3% vs. 54.8%, p = 0.026), and the incidence of adverse events was reduced by 36.3% (25% vs. 61.3%, p = 0.010) compared with the immunotherapy-alone group. Multicolor flow cytometry confirmed that the combination therapy significantly decreased the proportion of peripheral Tregs and increased the ratio of tissue-resident memory CD8+T cells (TRM) with effector function. In HCC-bearing mice, the combination therapy sensitized the anti-tumor effect of anti-PD-1 treatment, ameliorated immune-related hepatitis and nephritis induced by immunotherapy, enhanced the proportion, cytotoxicity, and proliferation of peripheral and tumor-infiltrating CD8+T cells, and markedly reduced the infiltration and proliferation of Tregs. Multi-omics analyses revealed that the combination therapy significantly downregulated the DHCR7-TFR1 signaling pathway, inhibiting lipotoxicity caused by excessive lipid accumulation in Tregs, which was identified as the central mechanism of the combination therapy for HCC. In vitro confirmed that FZJDXJ containing serum suppressed the activation of the DHCR7-TFR1 signaling pathway, inhibited excessive lipid accumulation in Tregs (detected by BODIPY493/503-FITC, Liperfluo, ROS, and MitoSOX), and attenuated the immunosuppressive capacity of Tregs and their secretion of TGF-βand IL-10 cytokines.</p><p>Conclusion: FZJDXJ enhances the efficacy of anti-PD-1 therapy for HCC by inhibiting Treg cholesterol metabolic reprogramming and lipotoxicity, thereby relieving the excessive immunosuppression of CD8+T cells by Tregs. This study provides a novel mechanism and clinical evidence for the combination of TCM compounds with immunotherapy for HCC.</p>
2025-12-05 | MTBLS13458 | MetaboLights
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.
2025-05-07 | PXD053108 | Pride
Project description:Background: Immune checkpoint inhibitors combined with antiangiogenic therapy has become the standard of care for advanced hepatocellular carcinoma, albeit with limited therapeutic benefit. Our previous studies demonstrated the immunomodulatory and antitumor effects of polyIC, a synthetic double-stranded RNA. Here, we compared the efficacy of anti-programmed death ligand 1 (?PD-L1) plus polyIC versus ?PD-L1 plus anti-vascular endothelial growth factor (?VEGF) in primary liver tumor models.Conclusion: This preclinical study identifies polyIC as a better enhancer of ?PD-L1 efficacy than ?VEGF in liver cancer, providing a novel strategy for improving immunotherapy outcomes. Further clinical investigation is warranted.
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Project description:The gut microbiome modulates immunotherapy treatment responses, and this may explain why immune checkpoint inhibitors (ICI), such as anti-PD-1, are only effective in some patients. Previous studies correlated lipopolysaccharide (LPS)-producing gut microbes with poorer prognosis; however, LPS from diverse bacterial species can range from immunostimulatory to inhibitory. By functionally analyzing fecal metagenomes from 112 melanoma patients, we found that a subset of LPS-producing bacteria encoding immunostimulatory hexa-acylated LPS was enriched in microbiomes of clinical responders. In an implanted tumor mouse model of anti-PD-1 treatment, microbiota-derived hexa-acylated LPS was required for effective anti-tumor immune responses, and LPS-binding antibiotics and a small molecule TLR4 antagonist abolished anti-PD-1 efficacy. Conversely, oral administration of hexa-acylated LPS to mice significantly augmented anti-PD-1-mediated anti-tumor immunity. Penta-acylated LPS did not improve anti-PD-1 efficacy in vivo and inhibited hexa-acylated LPS-induced immune activation in vitro. Microbiome hexa-acylated LPS therefore represents an accessible predictor and potential enhancer of immunotherapy responses.
2025-01-08 | MSV000096803 | MassIVE
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.
2024-07-07 | GSE267312 | GEO
Project description:The anti-PD-1 mAb is a type of immunotherapy known to have a significant impact on tumor immune components. In this study, we utilized single-cell RNA sequencing (scRNAseq) to analyze infiltrating immune cells of liver cancer in mice treated with both anti-PD-1 and isotype control.
2024-07-25 | GSE232023 | GEO
Project description:The efficacy of immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) treatment remains limited, warranting further investigation into the underlying mechanisms. Accumulating evidence indicates that myeloid cells within the tumor microenvironment (TME) play a role in immune evasion and treatment resistance. In this study, we aimed to explore the contribution of tumor-associated macrophages (TAMs) in the HCC TME. Our findings unveil the critical involvement of CX3C motif chemokine receptor 1 (CX3CR1)-positive TAMs in inducing T cell exhaustion through interleukin-27 (IL-27) secretion, providing valuable insights into the mechanisms underlying the suboptimal efficacy of anti-PD-1 therapy in HCC. Additionally, we identified prostaglandin E2 (PGE2) released by immune-attacked tumor cells as a key driver of CX3CR1+ TAM recruitment. To enhance the therapeutic response to current anti-PD-1 therapy, we propose a novel treatment strategy that combines targeted depletion of CX3CR1+ TAMs with anti-PD-1 therapy. Overall, our study contributes to the understanding of TAMs' role in cancer immunotherapy and presents potential clinical implications for HCC treatment. By targeting CX3CR1+ TAMs in conjunction with anti-PD-1 therapy, we have the potential to enhance the effectiveness of immunotherapeutic interventions in HCC patients.
2024-07-25 | GSE263240 | GEO
Project description:Melanoma is one of the most commonly diagnosed malignancies and serves as a model for studying immunotherapy. The B16 melanoma model is characterized by low T cell infiltration in the tumor, and blocking the PD-1 pathway shows no significant anti-tumor activity, mirroring melanoma patients with a cold tumor immunophenotype. Therefore, understanding the molecular basis that prevents T cell-mediated anti-tumor activity in B16 melanoma is of great significance. In this study, we generated Tyr knockout B16 melanoma cells using CRISPR/Cas9 and discovered that tyrosinase in melanoma significantly inhibits the anti-tumor activity of T cells. Tyrosinase deficiency significantly increases T-cell infiltration and activation within the tumor. Single-cell RNA sequencing reveals an altered cold tumor immunophenotype in tyrosinase-deficient B16 melanoma. In wild-type mice, T cells in tyrosinase-deficient tumors express elevated levels of PD-1 and Foxp3. However, strikingly, in PD-1 deficient mice, the loss of tyrosinase in B16 melanoma unleashes the anti-tumor activity of PD-1 deficient T cells. This enhanced anti-tumor activity is explained by significantly increased tumor T cell infiltration accompanied by reduced frequencies of Tregs in PD-1 knockout mice. Targeting tyrosinase may enhance the anti-tumor efficacy of PD-1 blockade in cold tumors, offering a novel strategy to render cold tumors responsive to immunotherapy. Clinically, higher levels of tyrosinase expression in human melanoma are associated with a poorer prognosis, indicating that our findings could potentially improve the efficacy of immunotherapy in melanoma patients.
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Project description:The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases for regulating PD-1 stability have been reported, deubiquitinase (DUB) governing PD-1 homeostasis to modulate tumor immunotherapy remains unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and stabilizes PD-1 through promoting PD-1/USP5 interaction. Conditional knockout (cKO) of Usp5 in T cells significantly suppresses tumor growth in mice largely through decreasing PD-1 and increasing tumor-infiltrating cytotoxic CD8+ T cells. Furthermore, co-targeting USP5 and ERK signaling has an additive effect on reducing PD-1 and suppressing tumor growth in vivo. Together, this study uncovers the molecular mechanism for ERK/USP5 axis in regulating PD-1 stability and identifies potential combined therapeutic strategies for enhancing anti-tumor efficacy.
2023-03-17 | PXD040671 |