Type I IFN innate immune response to adenovirus-mediated IFN-γ gene transfer contributes to the regression of cutaneous lymphomas
Mirjana Urosevic, Kazuyasu Fujii, Bastien Calmels, Elisabeth Laine, Nikita Kobert, Bruce Acres, Reinhard Dummer
Mirjana Urosevic, Kazuyasu Fujii, Bastien Calmels, Elisabeth Laine, Nikita Kobert, Bruce Acres, Reinhard Dummer
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Research Article Oncology

Type I IFN innate immune response to adenovirus-mediated IFN-γ gene transfer contributes to the regression of cutaneous lymphomas

Abstract

The fact that adenoviral vectors activate innate immunity and induce type I IFNs has not been fully appreciated in the context of cancer gene therapy. Type I IFNs influence different aspects of human immune response and are believed to be crucial for efficient tumor rejection. We performed transcriptional profiling to characterize the response of cutaneous lymphomas to intralesional adenovirus-mediated IFN-γ (Ad-IFN-γ) gene transfer. Gene expression profiles of skin lesions obtained from 19 cutaneous lymphoma patients before and after treatment with Ad-IFN-γ revealed a distinct gene signature consisting of IFN-γ– and numerous IFN-α–inducible genes (type II– and type I–inducible genes, respectively). The type I IFN response appears to have been induced by the vector itself, and its complexity, in terms of immune activation, was potentiated by the IFN-γ gene insert. Intralesional IFN-γ expression together with the induction of a combined type I/II IFN response to Ad-IFN-γ gene transfer seem to underlie the objective (measurable) clinical response of the treated lesions. Biological effects of type I IFNs seem to enhance those set in motion by the transgene, in our case IFN-γ. This combination may prove to be of therapeutic importance in cytokine gene transfer using Ads.

Authors

Mirjana Urosevic, Kazuyasu Fujii, Bastien Calmels, Elisabeth Laine, Nikita Kobert, Bruce Acres, Reinhard Dummer

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Figure 3

Ingenuity pathway analysis (IPA) of functional associations between IFN-γ– and IL-2–associated gene networks after Ad-null (A and C) and Ad-IFN-γ infection (B and D).

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Ingenuity pathway analysis (IPA) of functional associations between IFN-...
Each network is graphically displayed with genes/gene products as nodes (different shapes represent the functional classes of the gene products; see Node legend) and the biological relationships between the nodes as edges (lines). The length of an edge reflects the evidence in the literature supporting that node-to-node relationship. The intensity of the node color indicates the degree of up- (red) or downregulation (green) of the respective gene. IPA networks were generated as follows: Upon completed uploading of genes and corresponding fold-change expression values (done separately for Ad-IFN-γ and Ad-null differentially expressed genes), each gene identifier was mapped to its corresponding gene object in the IPA Knowledge Base (part of the IPA algorithm). Fold-change expression values were then used to identify genes whose expression was differentially regulated; these “focus genes” were overlaid onto a global molecular network contained in the IPA Knowledge Base. Networks of these focus genes were then algorithmically generated based on their connectivity and scored according to the number of focus genes within the network as well as according to the strength of their associations. We focused on IFNG- and IL-2–associated networks obtained after Ad-IFN-γ infection. To show the difference in genes expressed after infection with Ad-null, these networks were overlaid with Ad-null data. It is of note that the networks obtained after Ad-null infection lacked expression of several genes (white nodes) differentially regulated by Ad-IFN-γ.