Genomics

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IL-12 Virotherapy Induces Immune Equilibrium in Melanoma That is Overcome by Blockade of Innate Inflammatory Cytokine


ABSTRACT: Viral vectors deliver therapeutic cargo with the natural adjuvant effect of a pathogen. We engineered a non-replicating herpes simplex virus 1, d106S-IL12, to deliver IL-12 to the tumor microenvironment, resulting in a type I interferon response, rapid production of T cell recruiting chemokines, and accumulation of melanoma-specific CD8 T cells. We immunologically defined a long-term, stable immune equilibrium, whereby mice neither succumbed nor fully cleared their tumors. We profiled the immune equilibrium induced by d106S-IL12, identifying blockade of innate inflammatory cytokines, TNFα, IL-1β, or IL-6 as possible synergistic interventions. Single-cell RNA-sequencing demonstrated that d106S-IL12 induced a loss of Tregs and a shift towards Th1 responses, while blockade of inflammatory cytokines repolarized macrophages towards a less suppressive phenotype. Blockade of each cytokine resulted in downregulation of overlapping inflammatory pathways, shifting immune equilibrium towards tumor clearance. These results suggest targeting innate inflammatory cytokines could enhance immunotherapy efficacy while potentially mitigating toxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE160132 | GEO | 2023/07/18

REPOSITORIES: GEO

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