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Spatial transcriptomics of mouse lung after tumor induction.

ABSTRACT: Resistance to immune checkpoint blockade (ICB) remains a major barrier in non-small cell lung cancer (NSCLC), where defective antigen presentation, myeloid-cell dominance, and immune exclusion limit anti-tumor immunity. Here, we show that IL-12/FLT3L-armed dendritic-cell progenitors (DCPs) overcome these barriers by reprogramming the tumor microenvironment into an immune-responsive ecosystem dominated by interferon (IFN)-IRF1 signaling, which unlocked both chemo-immunotherapy and CAR-T efficacy in autochthonous and orthotopic KrasG12D;Trp53−/− lung tumors. DCP monotherapy triggered an IFN-stimulated gene (ISG) circuit operative across cellular compartments, while combination therapy enhanced tumor regression independent of MHC-I expression in cancer cells or CD8 T cell cytotoxicity. This response involved the expansion of IFNγ⁺ T and NK cells, inflammatory monocytes, ISG-polarized neutrophils, and immune-stimulatory fibroblasts, coupled with depletion of Tregs, immunosuppressive neutrophils, myofibroblasts, and angiogenic endothelial cells. IFNγ neutralization abrogated the therapeutic response, underscoring its central role in orchestrating cross-compartmental reprogramming. IRF1 was concordantly expressed across epithelial, immune, and stromal compartments in human cancer and correlated with ICB response, highlighting the relevance of DCP-induced inflammatory programs in cancer control.

ORGANISM(S): Mus musculus

PROVIDER: GSE341382 | GEO | 2026/09/15

REPOSITORIES: GEO

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Project description:Interferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-γ/glucose and increased IFITM3 in galactose by IFN-α and IFN-γ. In agreement with a hardwired response, glucose/galactose regulation of interferon-γ induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-γ induced IRF1 levels to that of glucose/interferon-γ. Glucose/interferon-γ decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored by IRF1 KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT and IRF1 KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN-γ priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.

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Spatial transcriptomics of mouse lung after tumor induction.

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