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Immune-stimulating antibody conjugates elicit robust myeloid activation and durable anti-tumor immunity II

ABSTRACT: Innate pattern recognition receptors, including toll-like receptors (TLRs), can alter the tumor microenvironment and prime adaptive anti-tumor immunity. However, TLR agonists have not been well-tolerated due to toxicities associated with widespread immune activation following systemic administration. To design a therapeutic that is suitable for systemic delivery and capable of eliciting a tumor-targeted response, we developed a novel class of immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 agonist conjugated to tumor-targeting antibodies. Systemically administered anti-HER2 ISACs were well-tolerated in vivo and elicited robust activation of intratumoral myeloid cells, resulting in tumor clearance and subsequent immunological memory. In vitro potency and in vivo efficacy required tandem activity driven by intact Fc functionality and TLR agonism to enable phagocytosis and T cell-mediated anti-tumor immunity. ISAC-mediated immunological memory was not limited to HER2, as ISAC-treated mice were protected from rechallenge with a HER2-negative tumor. These results provide strong rationale for the clinical development of ISACs and show that synergy between FcgR and TLR7/8 signaling contributes to the mechanism of ISAC-mediated anti-tumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE157869 | GEO | 2020/12/03

REPOSITORIES: GEO

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Immune-stimulating antibody conjugates elicit robust myeloid activation and durable anti-tumor immunity I

Project description:Innate pattern recognition receptors, including toll-like receptors (TLRs), can alter the tumor microenvironment and prime adaptive anti-tumor immunity. However, TLR agonists have not been well-tolerated due to toxicities associated with widespreadimmune activation following systemic administration. To design a therapeutic that is suitable for systemic delivery and capable of eliciting a tumor-targeted response, we developed a novel class of immune-stimulating antibody conjugates (ISACs) comprising a TLR7/8 agonist conjugated to tumor-targeting antibodies. Systemically administered anti-HER2 ISACs were well-tolerated in vivo and elicited robust activation of intratumoral myeloid cells, resulting in tumor clearance and subsequent immunological memory. In vitro potency and in vivo efficacy required tandem activity driven by intact Fc functionality and TLR agonism to enable phagocytosis and T cell-mediated anti-tumor immunity. ISAC-mediated immunological memory was not limited to HER2, as ISAC-treated mice were protected from rechallenge with a HER2-negative tumor. These results provide strong rationale for the clinical development of ISACs and show that synergy between FcgR and TLR7/8 signaling contributes to the mechanism of ISAC-mediated anti-tumor immunity.

2020-12-03 | GSE157848 | GEO

Gene profiling in the colon after depletion and activation of TLR3 and TLR7 signals

Project description:TLR3 and TLR7 are critical recognition receptor which reacts with viruses. TLR3 and TLR7 contribute to many immunological pathway. Especially, TLR3 and TLR7 are clearly involved in the regulation of innate immunity in the gut. To identify the downstream target of TLR 3 and TLR7 in the IBD, we carried out microarray. The colon tissues were isolated from four different groups. None-no treatment, after DSS treated, after DSS+antiviral treatment, after DSS+TLR3+7 agonists.

2016-07-05 | E-GEOD-79241 | biostudies-arrayexpress

Gene profiling in the colon after depletion and activation of TLR3 and TLR7 signals

2016-07-05 | GSE79241 | GEO

Transcription profiling of human dendritic cells and monocytes treated with anti-FcgRIIb

Project description:The ability of dendritic cells (DCs) to activate immunity is linked to their maturation status. In prior studies we have shown that selective antibody-mediated blockade of inhibitory FcgRIIB receptor on human DCs in the presence of activating immunoglobulin (Ig) ligands leads to DC maturation and enhanced immunity to antibody-coated tumor cells. Here we show that Fcg receptor (FcgR) mediated activation of human monocytes and monocyte-derived DCs is associated with a distinct gene expression pattern, including several inflammation associated chemokines as well as type 1 interferon (IFN) response genes including the activation of signal transducer and activator of transcription 1 (STAT1). Experiment Overall Design: To further characterize FcgR mediated enhancement of DC function, we analyzed the gene expression profiles (GEP) of pure populations of monocyte-derived DCs from healthy donors (n=5) using Affymetrix Human Genome U133 Plus2.0 microarrays. Immature DCs cultured in 1% plasma were treated for 24 hours with either anti-FcgRIIB or isotype control antibody. To test whether FcgR mediated DC maturation was distinct from other maturation stimuli, we also compared DCs matured using the inflammatory cytokine cocktail (TNF-a, IL-1b, IL-6 and PGE2) commonly utilized in DC immunotherapy trials. In addition, we also treated Cd14+ monocytes (n=3) with anti-FcgRIIB antibody or isotype control. In order to better characterize the interferon responsive genes in DCs, we treated immature DCs (n=3) with 1000 U/ml of IFN-a2b.

2008-06-15 | E-GEOD-7509 | biostudies-arrayexpress

Carbon ion irradiation plus CTLA4 blockade elicits therapeutic immune responses in a murine tumor model

Project description:Radiotherapy can act as in situ vaccine activating preventive tumor-specific immune responses in treated patients. While carbon ion radiotherapy holds superior biophysical properties over conventional photon irradiation, little is known about the immunological effects induced by this radiation type. Multiple strategies combining radiotherapy with immune checkpoint inhibition (radioimmunotherapy) to enhance anti-tumor immunity have been described, however, results on the immune cell composition in tumors following radioimmunotherapy with carbon ions are lacking. Here, we present a bilateral tumor model based on time-shifted transplantation of murine, Her2+ EO771 tumor cells onto the flanks of immune competent mice followed by selective irradiation of the primal tumor. αCTLA4- but not αPD-L1-based radioimmunotherapy induced complete tumor rejection and mediated eradication of even non-irradiated, distant tumors. Cured mice were protected against EO771 rechallenge indicative of long lasting, tumor-specific immunological memory. Single cell RNA-sequencing and flow cytometric analyses of irradiated tumors revealed activation of NK cells and distinct tumor-associated macrophage clusters with upregulated expression of TNF and IL1 responsive genes. Distant tumors of irradiated mice showed higher frequencies of naïve T cells, which were activated upon combination with CTLA4 blockade. Thus, radioimmunotherapy with carbon ions plus CTLA4 inhibition reshapes the tumor-infiltrating immune cell composition and can induce complete rejection even of non-irradiated tumors. Our data suggest to combine radiotherapy approaches with CTLA4 blockade to achieve durable anti-tumor immunity. Furthermore, evaluation of future radioimmunotherapy approaches should not be restricted to immunological impacts at the irradiation site, but should also consider systemic immunological effects on non-irradiated tumors.

2022-09-30 | GSE214524 | GEO

ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory (expression)

Project description:Immunological memory is generally thought to be mediated exclusively by lymphocytes such as memory T and B cells. However, enhanced innate immune responses caused by a previous infection increase protection against reinfection suggesting the presence of innate immunological memory. Here, we describe expression profile of peritoneal macrophages from wild-type mice pre-administrated with TLR ligands or from ATF7 knockout mice. ATF7 suppresses a group of innate-immunity genes in macrophage by recruiting H3K9 dimethyltransferase G9a. TLR ligands induce ATF7 phosphorylation, leading to release of ATF7 from chromatin and reduction in H3K9me2 level. Partially disrupted chromatin structure and increased basal expression on target genes are maintained for a long period, increasing resistance pathogens. Therefore we speculate ATF7 is important factor in controlling innate immunological memory. This series contains seven sets of exression array data. For all sample, we use four CEL files generated by four biological-independent experiments.

2015-08-31 | E-GEOD-71111 | biostudies-arrayexpress

Sustained R848 treatment of Mice

Project description:PCR Array Profiling - R848 does not induce TLR-signaling related genes in TLR7-/- mice. Aim: To corroborate TLR7-dependency of R848 in mice "Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology", Baenziger et al. Blood 2008

2008-09-30 | GSE12957 | GEO

BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity

Project description:BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity

| PRJNA765317 | ENA

Bruton's Tyrosine Kinase Regulates TLR9 but not TLR7 Signaling in Human pDCs

Project description:Plasmacytoid dendritic cells (pDCs) can be activated by the endosomal TLRs, and contribute to the pathogenesis of systemic lupus erythematosus (SLE) by producing type I IFNs. Thus, blocking TLR-mediated pDC activation may represent a useful approach for the treatment of SLE. In an attempt to identify a therapeutic target for blocking TLR signaling in pDCs, we investigated the contribution of Bruton's tyrosine kinase (Btk) to the activation of pDCs by TLR7 and TLR9 stimulation by using a selective Btk inhibitor RN486. Stimulation of TLR7 and 9 with their respective agonist, namely, gardiquimod and type A CpG ODN2216, resulted in the activation of human pDCs, as demonstrated by the expression of activation markers (CD69, CD40, and CD86), elevated production of IFN-alpha and other inflammatory cytokines, as well as up-regulation of numerous genes including IFN-alpha-inducible genes and activation of interferon regulatory factor 7 (IRF7) and NF-kB. RN486 inhibited all of these events induced by TLR9, but not TLR7 stimulation, with a nanomolar potency for inhibiting type A CpG ODN2216-mediated production of cytokines (e.g., IC50=386 nM for inhibiting IFN-alpha). Our data reveal Btk as an important regulatory enzyme in the TLR9 pathway, and a potential therapeutic target for SLE and other TLR-driven diseases. pDCs from healthy donors (n=4) were treated with gardiquimod (TLR7 agonist) or ODN 2216 (TLR9 agonist) with or without BTK inhibitor for 3 hours.

2015-10-24 | E-GEOD-41825 | biostudies-arrayexpress

ATF7 mediates lipopolysaccharide-induced epigenetic changes in macrophages involved in innate immunological memory (expression)

2015-08-31 | GSE71111 | GEO

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