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Integration of tumor-specific dendritic cell and antibody therapy within tumor drives innate and adaptive anti-cancer immunity [PanCancer_IO360_NanoString]

ABSTRACT: Comparison of gene expression profiles of HER2+ murine mammary carcinoma treated with HER2 DC1, anti-Sema4D, and combination of both HER2 DC1 and anti-Sema4D therapy

ORGANISM(S): Mus musculus

PROVIDER: GSE302765 | GEO | 2026/02/02

REPOSITORIES: GEO

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Integration of tumor-specific dendritic cell and antibody therapy within tumor drives innate and adaptive anti-cancer immunity [Metabolic_Pathways_NanoString]

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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.

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