Exercise inhibits tumor progression and improves the therapeutic efficacy of PD-1 blockade in colorectal cancer preclinical models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA722267 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14244176.fastq.gz | Fastqsanger.gz | |||
| SRR14244177.fastq.gz | Fastqsanger.gz | |||
| SRR14244178.fastq.gz | Fastqsanger.gz | |||
| SRR14244179.fastq.gz | Fastqsanger.gz | |||
| SRR14244180.fastq.gz | Fastqsanger.gz |
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Project description:Exercise training (ExT) has shown antitumor effects in many preclinical cancer models. In the present study, we utilize MC38 and CT26 cells, which represent MSI and MSS colorectal carcinomas respectively, to study the effects and mechanisms of ExT alone or in combination with PD-1 based immunotherapy. Using treadmill running and PD-1/PD-L1 blockade, we demonstrated that post-implant exercise training has broad anticancer activities in murine models of CRC. Specifically, in MSI CRC models, ExT induces beneficial metabolic and immunological adaptations, leading to a more significant inhibition in tumors treated with PD-1/PD-L1 blockade, suggesting a genotype-directed combinatory therapy for the subgroup of CRC patients. Moreover, ExT might be a safe and alternative anticancer strategy for cancers resistant to the PD-1 based immunotherapy, such as patients with MSS CRC tumors.
2021-04-16 | GSE172162 | GEO
Project description:We found that PMN-MDSCs level is elevated in the advanced ICCs tissues and is positively associated with the METTL1 and m7G tRNA modification levels. We further showed that impaired m7G tRNA modification impedes the PMN-MDSCs infiltration and inhibits ICC progression. Mechanistically, METTL1-mediated m7G tRNA modification selectively regulates the translation of human CXCL8 and mouse Cxcl5 transcripts, which facilitates the migration of PMN-MDSCs via binding to their cognate receptor CXCR2. Co-blockade of METTL1 and CXCR2 significantly enhances the efficacy of anti-PD-1 treatment in ICC. Taken together, our study reveals the cellular and molecular basis of crosstalk between ICC cells and MDSCs in shaping TIME and affecting ICIs efficacy, which enables reasonable design of new combined therapy targeting dysregulated mRNA translation and suppressive TIME.
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Project description:Therapeutic efficacy of FASN inhibition in preclinical models of HCC
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Project description:Drugs used to treat obesity and type 2 diabetes have limited efficacy in directly normalising muscle metabolism. The discovery of molecules mediating exercise adaptations, and drugs that modulate their activity, is a potential strategy to address this therapeutic gap. Here we show that genetic impairment of HDAC4 and 5 in mice regulated a subset of exercise responsive genes involved in metabolism and increased cell autonomous energy expenditure. Screening of HDAC inhibitors identified Scriptaid as a compound that also replicated aspects of the exercise adaptive response in vitro and in vivo. Treatment of obese mice with Scriptaid increased exercise performance, restored muscle insulin sensitivity and reduced muscle lipids. Scriptaid also increased oxygen consumption and normalised cardiac structure and function in obese mice. These data show that HDAC inhibition replicates aspects of the exercise adaptive response and that pharmacological HDAC inhibition could deliver more efficacious treatment to combat the metabolic diseases. Four-condition experiment, Empty, HDACs, Vehicle and Script-HDACs with five biological replicates for each condition. One replicate per array.
2015-01-28 | E-GEOD-54642 | biostudies-arrayexpress
Project description:Receptor activator of NF-?B ligand (RANKL) and its receptor RANK, are members of the tumor necrosis factor and receptor superfamilies, respectively. Antibodies targeting RANKL have recently been evaluated in combination with anti-CTLA4 in case reports of human melanoma and mouse models of cancer. However, the efficacy of anti-RANKL in combination with antibodies targeting other immune checkpoint receptors such as PD1 has not been reported. In this study, we demonstrated that blockade of RANKL improves anti-metastatic activity of antibodies targeting PD1/PD-L1 and improves subcutaneous growth suppression in mouse models of melanoma, prostate and colon cancer. Suppression of experimental lung metastasis following combination anti-RANKL with anti-PD1 requires NK cells and IFN-?, whereas subcutaneous tumor growth suppression with this combination therapy is attenuated in the absence of T cells and IFN-?. Furthermore, addition of anti-RANKL to anti-PD1 and anti-CTLA4 resulted in superior anti-tumor responses, irrespective of the ability of anti-CTLA4 isotype to engage activating FcR, and concurrent or delayed RANKL blockade was most effective. Early-during-treatment assessment reveals this triple combination therapy compared to dual anti-PD1 and anti-CTLA4 combination therapy further increased the proportion of tumor-infiltrating CD4+ and CD8+ T cells that can produce both IFN-? and TNF. Finally, RANKL expression appears to identify tumor-specific CD8+ T cells expressing higher levels of PD1 which can be modulated by anti-PD1. These data set the scene for clinical evaluation of denosumab use in patients receiving contemporary immune checkpoint blockade.
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Project description:BackgroundDysregulated expression and activation of receptor tyrosine kinases (RTKs) are associated with a range of human cancers. However, current RTK-targeting strategies exert little effect on pancreatic cancer, a highly malignant tumor with complex immune microenvironment. Given that immunotherapy for pancreatic cancer still remains challenging, this study aimed to elucidate the prognostic role of RTKs in pancreatic tumors with different immunological backgrounds and investigate their targeting potential in pancreatic cancer immunotherapy.MethodsKaplan-Meier plotter was used to analyze the prognostic significance of each of the all-known RTKs to date in immune "hot" and "cold" pancreatic cancers. Gene Expression Profiling Interactive Analysis-2 was applied to assess the differential expression of RTKs between pancreatic tumors and normal pancreatic tissues, as well as its correlation with immune checkpoints (ICPs). One hundred and fifty in-house clinical tissue specimens of pancreatic cancer were collected for expression and correlation validation via immunohistochemical analysis. Two pancreatic cancer cell lines were used to demonstrate the regulatory effects of RTKs on ICPs by biochemistry and flow cytometry. Two in vivo models bearing pancreatic tumors were jointly applied to investigate the combinational regimen of RTK inhibition and immune checkpoint blockade for pancreatic cancer immunotherapy.ResultsMET was identified as a pancreatic cancer-specific RTK, which is significantly associated with prognosis in both immune "hot" and "cold" pancreatic cancers. MET was observed to be highly upregulated in pancreatic cancer tissues, and positively correlated with PD-L1 levels. Elevated MET and PD-L1 expressions were closely associated with lymph node metastasis, tumor TNM stage, and overall survival in pancreatic cancer. Mechanistically, MET could interact with PD-L1, and maintain its expression level in multiple ways. MET deficiency was found to facilitate lymphocyte infiltration into pancreatic tumors. Finally, significant benefits of combining MET inhibition with PD-1/PD-L1 blockage were verified in both orthotopic and subcutaneous mouse models of pancreatic cancer.ConclusionsThis study systematically investigated the potential effectiveness of a novel pancreatic cancer immunotherapy targeting RTKs, and revealed the function of MET in PD-L1 regulation as well as the combined therapeutic efficacy of MET and PD-L1 in pancreatic cancer.
| S-EPMC8414725 | biostudies-literature
Project description:Background & Aims: Aberrant activation of fatty acid synthase (FASN) is a major metabolic event during the development of HCC. We evaluated the therapeutic efficacy of TVB3664, a novel FASN inhibitor, either alone or in combination, for HCC treatment. Approach & Results: The therapeutic efficacy and the molecular pathways targeted by TVB3664, either alone or with tyrosine kinase inhibitors or the checkpoint inhibitor anti-PD-L1 antibody, were assessed in human HCC cell lines and multiple oncogene-driven HCC mouse models. RNAseq was performed to characterize the global gene expression and metabolic profiles. TVB3664 effectively ameliorated the fatty liver phenotype in the aged mice and AKT activation-induced hepatic steatosis. TVB3664 monotherapy showed moderate efficacy in NASH-related murine HCCs, induced by loss of PTEN and c-MET overexpression. TVB3664, in combination with cabozantinib, triggered tumor regression in this mouse HCC model but did not improve the responsiveness to immunotherapy. Global gene expression revealed that TVB3664 predominantly modulated metabolic processes, while TVB3664 synergized with cabozantinib to downregulate multiple cancer-related pathways, especially the AKT/mTOR pathway and cell proliferation genes. TVB3664 also improved the therapeutic efficacy of sorafenib and cabozantinib in the FASN-dependent c-MYC HCC model. However, TVB3664 had no efficacy nor synergistic effects in FASN-independent mouse HCC models. Conclusions: This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment.
2022-01-28 | GSE189529 | GEO
Project description:Blockade of immune checkpoint pathways by programmed cell death protein 1 (PD-1) antibodies has demonstrated broad clinical efficacy against a variety of malignancies. Sintilimab, a highly selective, fully human monoclonal antibody (mAb), blocks the interaction of PD-1 and its ligands and has demonstrated clinical benefit in various clinical studies. Here, we evaluated the affinity of sintilimab to human PD-1 by surface plasmon resonance and mesoscale discovery and evaluated PD-1 receptor occupancy and anti-tumor efficacy of sintilimab in a humanized NOD/Shi-scid-IL2rgamma (null) (NOG) mouse model. We also assessed the receptor occupancy and immunogenicity of sintilimab from clinical studies in humans (9 patients with advanced solid tumor and 381 patients from 4 clinical studies, respectively). Sintilimab bound to human PD-1 with greater affinity than nivolumab (Opdivo®, MDX-1106) and pembrolizumab (Keytruda®, MK-3475). The high affinity of sintilimab is explained by its distinct structural binding mode to PD-1. The pharmacokinetic behavior of sintilimab did not show any significant differences compared to the other two anti-PD-1 mAbs. In the humanized NOG mouse model, sintilimab showed superior PD-1 occupancy on circulating T cells and a stronger anti-tumor effect against NCI-H292 tumors. The strong anti-tumor response correlated with increased interferon-?-secreting, tumor-specific CD8+ T cells, but not with CD4+ Tregs in tumor tissue. Pharmacodynamics testing indicated a sustained mean occupancy of ?95% of PD-1 molecules on circulating T cells in patients following sintilimab infusion, regardless of infusion dose. Sintilimab infusion was associated with 0.52% (2/381 patients) of anti-drug antibodies and 0.26% (1/381 patients) neutralizing antibodies. These data validate sintilimab as a novel, safe, and efficacious anti-PD-1 mAb for cancer immunotherapy.
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Project description:Drugs used to treat obesity and type 2 diabetes have limited efficacy in directly normalising muscle metabolism. The discovery of molecules mediating exercise adaptations, and drugs that modulate their activity, is a potential strategy to address this therapeutic gap. Here we show that genetic impairment of HDAC4 and 5 in mice regulated a subset of exercise responsive genes involved in metabolism and increased cell autonomous energy expenditure. Screening of HDAC inhibitors identified Scriptaid as a compound that also replicated aspects of the exercise adaptive response in vitro and in vivo. Treatment of obese mice with Scriptaid increased exercise performance, restored muscle insulin sensitivity and reduced muscle lipids. Scriptaid also increased oxygen consumption and normalised cardiac structure and function in obese mice. These data show that HDAC inhibition replicates aspects of the exercise adaptive response and that pharmacological HDAC inhibition could deliver more efficacious treatment to combat the metabolic diseases.
2015-01-28 | GSE54642 | GEO