Project description:Treating samples with anti-CD40, and antibiotics to establish what transcriptional impact antibiotics is having. Anti-CD40 was found to induce a strong inflammatory signature. Antibiotics in combination with anti-CD40 attenuated this resulting in a much improved phenotype. However the detectable transcriptional differences were somewhat modest.
Project description:Temporal analysis (60, 180, 360 min) of B cells treated with either: CD40 Anti-IgM ELC IL4 Lipopolysaccharide Terbutaline CD40 and IL4 CD40 and Lipopolysaccharide CD40 and Anti-IgM Anti-IgM and ELC Anti-IgM and Terbutaline ELC and Lipopolysaccharide This SuperSeries is composed of the following subset Series: GSE1019: B cell response to Anti-IgM and CD40 treatment GSE1020: B cell response to Anti-IgM and ELC treatment GSE1021: B cell response to Anti-IgM and terbutaline treatment GSE1022: B cell response to CD40 and lipopolysaccharide treatment GSE1023: B cell response to CD40 and IL4 treatment GSE1024: B cell response to ELC and lipopolysaccharide treatment Refer to individual Series
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
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.
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.
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.
Project description:Temporal analysis (60, 180, 360 min) of B cells treated with either: CD40 Anti-IgM ELC IL4 Lipopolysaccharide Terbutaline CD40 and IL4 CD40 and Lipopolysaccharide CD40 and Anti-IgM Anti-IgM and ELC Anti-IgM and Terbutaline ELC and Lipopolysaccharide This SuperSeries is composed of the SubSeries listed below.
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.