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Evaluating CD40 Agonist Alone and in Combination with IL-1R1 Blockade in Pancreatic Cancer

ABSTRACT: Evaluating CD40 Agonist Alone and in Combination with IL-1R1 Blockade in Pancreatic Cancer

PROVIDER: PRJNA1285956 | ENA |

REPOSITORIES: ENA

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Evaluating CD40 Agonist Alone and in Combination with IL-1R1 Blockade in Pancreatic Cancer

Project description:To investigate the immunomodulatory effects of IL-1R1 blockade in pancreatic ductal adenocarcinoma (PDAC), we performed bulk RNA sequencing of tumors subjected to distinct treatment regimens. Tumors were treated with either an anti–IL-1R1 antibody or left untreated, and another cohort received combination therapy with agonistic CD40 and anti–IL-1R1 antibodies versus CD40 agonist monotherapy. Gene ontology enrichment analysis of differentially expressed genes (p ≤ 0.05) revealed that anti–IL-1R1 treatment upregulated genes involved in RNA processing, including spliceosome-associated pathways, compared with untreated controls. Conversely, immune-related pathways—such as response to type II interferon, leukocyte-mediated immunity, and T-cell activation—were significantly downregulated in the anti–IL-1R1 group. In contrast, tumors receiving combination therapy exhibited enhanced innate and adaptive immune signatures compared to CD40 monotherapy, including antigen presentation, lymphocyte-mediated immunity, and regulation of immune effector functions. Metabolic pathways were notably downregulated in the combination group. Gene set enrichment analysis further confirmed the upregulation of key immune pathways, including NOD-like receptor signaling, NF-κB signaling, NK cell–mediated cytotoxicity, and JAK-STAT signaling, in the combination therapy group. These findings highlight the context-dependent effects of IL-1R1 blockade and support its synergistic potential with CD40 agonism in modulating the PDAC tumor microenvironment.

2025-07-25 | GSE301673 | GEO

TNF blockade uncouples toxicity and anti-tumor efficacy induced with an agonist CD40 antibody

Project description:TNF mechanistically links cytokine release and hepatotoxicity triggered by an agonist CD40 antibody, and toxicity can be suppressed by blockade of TNF without affecting anti-tumor efficacy.

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PPARδ inhibition blocks tumor-induced Bregs and enhances CD40 agonist immunotherapy

Project description:Most cancers are cold tumors characterized by a lack of effector T cells and hence unresponsive to immune checkpoint blockades, highlighting the importance of repairing the failed T cell priming in cancer immunotherapy. CD40 agonists are efficient in eliciting T cell responses and effective in converting cold tumors into hot, their clinical application, however, is limited by the very narrow window between the effective and toxic dosages. Here, we sought to reduce the effective dosage of CD40 agonists by combination therapy. We identified a CD19+CD24hiCD38lowIgDlow/- regulatory B cell (Breg) subset that is increased in tumor-bearing mice and cancer patients, and discovered that PPARδ is highly expressed in these tumor-associated Bregs and required for their proliferation and function. Inhibition of PPARδ acted synergistically with agonist anti-CD40 to enhance antitumor immunity without increasing toxicity in murine melanoma and bladder carcinoma models. Combination therapy with PPARδ inhibitor could reduce anti-CD40 dosage by over 60% to a well-tolerated level with improved or at least not compromised antitumor effects, providing a potential strategy for safely using CD40 agonists in cancer treatment. PPARδ also offers a new target for selectively blocking Breg activity while sparing immunostimulatory B cells that are known to aid antitumor immunotherapy.

2024-02-20 | GSE168523 | GEO

TNF blockade uncouples toxicity and anti-tumor efficacy induced with an agonist CD40 antibody

Project description:TNF blockade uncouples toxicity and anti-tumor efficacy induced with an agonist CD40 antibody

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B cell response to CD40 and IL4 treatment

Project description:Temporal analysis (60, 180, 360 min) of B cells treated with CD40 alone, IL4 alone or CD40 and IL4 (all in triplicates). Keywords: other

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B cell response to CD40 and lipopolysaccharide treatment

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PPARδ inhibition blocks tumor-induced Bregs and enhances CD40 agonist immunotherapy

Project description:PPARδ inhibition blocks tumor-induced Bregs and enhances CD40 agonist immunotherapy

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Project description:Temporal analysis (60, 180, 360 min) of B cells treated with Anti-IgM alone, CD40 alone or Anti-IgM and CD40 (all in triplicates). Keywords: other

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RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of neonatal rat ventricular myocytes (NRVM) to adrenergic receptor agonist phenylephrine (PE)

Project description:RNA-seq analysis evaluating effects of Cdk7 inhibitor THZ1 on responses of NRVM to adrenergic receptor agonist PE

2022-04-25 | GSE151253 | GEO

Pro-immunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy [MC38 treated with MEKi, CD40, in vivo]

Project description:Cancer types with lower mutational load and a non-permissive tumor microenvironment are intrinsically resistant to immune checkpoint blockade. While the combination of cytostatic drugs and immunostimulatory antibodies constitutes an attractive concept for overcoming this refractoriness, suppression of immune cell function by cytostatic drugs may limit therapeutic efficacy. Here we show that targeted inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK) does not impair dendritic cell-mediated T-cell priming and activation. Accordingly, combining MEK inhibitors (MEKi) with agonist antibodies (Abs) targeting the immunostimulatory CD40 receptor resulted in potent synergistic anti-tumor efficacy. Detailed analysis of the mechanism of action of MEKi GDC-0623 by means of flow cytometric analysis of the tumor immune infiltrate and whole tumor transcriptomics showed that, in addition to its cytostatic impact on tumor cells, this drug exerts multiple pro-immunogenic effects, including the suppression of M2-type macrophages, myeloid derived suppressor cells and CD4+ T-regulatory cells. In addition, MEKi was found to induce tumor-cell intrinsic interferon signaling, which contributed to antigen presentation by tumor cells. Finally, the tumoridical impact of MEKi involves the activation of multiple pro-inflammatory pathways involved in immune cell effector function in the tumor microenvironment. Our data therefore indicate that the combination of MEK inhibition with agonist anti-CD40 Ab is a promising therapeutic concept, especially for the treatment of mutant Kras-driven tumors such as pancreatic ductal adenocarcinoma. We used microarrays to monitor transcriptional and cell-type composition changes in murine transplantable tumor models of pancreatic ductal adenocarcinoma (PDA30364), colon cancer (MC38) and melanoma (B16-OVA) upon treatment with MEK inhibitor (GDC-0623), anti-CD40 antibody or the combination of GDC-0623 and anti-CD40 antibody.

2020-01-24 | GSE144139 | GEO

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