TNF blockade uncouples toxicity and anti-tumor efficacy induced with an agonist CD40 antibody
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA656939 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12445163.fastq.gz | Fastqsanger.gz | |||
| SRR12445164.fastq.gz | Fastqsanger.gz | |||
| SRR12445165.fastq.gz | Fastqsanger.gz | |||
| SRR12445166.fastq.gz | Fastqsanger.gz | |||
| SRR12445167.fastq.gz | Fastqsanger.gz |
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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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Project description:The goal of this study was to identify through NGS transcriptomic (RNAseq), transcripts up and down-regulated, following the i.v. treatment of B-ALL Patient-Derived Xenotransplanted (PDX) mice (two models; #1 and #2) with anti-CD40 agonist antibody.
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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.
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Project description:PPARδ inhibition blocks tumor-induced Bregs and enhances CD40 agonist immunotherapy
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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), chemotherapeutic agent gemcitabine (GEM), anti-CD40 antibody or the combination of GDC-0623 or chemotherapy Gemcitabine (GEM) and anti-CD40 antibody.
2020-01-27 | GSE144128 | GEO
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
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 | GSE144145 | GEO
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.
2020-02-05 | GSE144570 | GEO
Project description:BackgroundCD40 is a 48 kDa type I transmembrane protein that is constitutively expressed on hematopoietic cells such as dendritic cells, macrophages, and B cells. Engagement of CD40 by CD40L expressed on T cells results in the production of proinflammatory cytokines, induces T helper cell function, and promotes macrophage activation. The involvement of CD40 in chronic immune activation has resulted in CD40 being proposed as a therapeutic target for a range of chronic inflammatory diseases. CD40 antagonists are currently being explored for the treatment of autoimmune diseases and several anti-CD40 agonist mAbs have entered clinical development for oncological indications.ResultsTo better understand the mode of action of anti-CD40 mAbs, we have determined the x-ray crystal structures of the ABBV-323 (anti-CD40 antagonist, ravagalimab) Fab alone, ABBV-323 Fab complexed to human CD40 and FAB516 (anti-CD40 agonist) complexed to human CD40. These three crystals structures 1) identify the conformational CD40 epitope for ABBV-323 recognition 2) illustrate conformational changes which occur in the CDRs of ABBV-323 Fab upon CD40 binding and 3) develop a structural hypothesis for an agonist/antagonist switch in the LCDR1 of this proprietary class of CD40 antibodies.ConclusionsThe structure of ABBV-323 Fab demonstrates a unique method for antagonism by stabilizing the proposed functional antiparallel dimer for CD40 receptor via novel contacts to LCDR1, namely residue position R32 which is further supported by a closely related agonist antibody FAB516 which shows only monomeric recognition and no contacts with LCDR1 due to a mutation to L32 on LCDR1. These data provide a structural basis for the full antagonist activity of ABBV-323.
| S-EPMC6683420 | biostudies-literature