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Diverse Anti-Tumor Immune Potential Driven by Individual IFN? Subtypes.

ABSTRACT: Immunotherapies harnessing T cell immunity have shown remarkable clinical success for the management of cancer. However, only a proportion of patients benefit from these treatments. The presence of type I interferon (IFN) within the tumor microenvironment is critical for driving effective tumor-specific T cell immunity. Individuals can produce 12 distinct subtypes of IFN?, which all signal through a common receptor. Despite reported differences in anti-viral potencies, the concept that distinct IFN? subtypes can improve anti-cancer treatments remains unclear. We tested whether expression of unique IFN? subtypes confined to the tumor microenvironment enhances tumor control. This was systematically evaluated by transplantation of B16 murine melanoma cells secreting five unique IFN? subtypes (B16_IFN?2; B16_IFN?4; B16_IFN?5; B16_IFN?6; B16_IFN?9) into a pre-clinical murine model. We show that IFN?2 and IFN?9 are the only subtypes capable of completely controlling tumor outgrowth, with this protection dependent on the presence of an adaptive immune response. We next determined whether these differences extended to other model systems and found that the adoptive transfer of tumor-specific CD8+ T cells engineered to secrete IFN?9 delays tumor growth significantly and improves survival, whereas no enhanced survival was observed using T cells secreting IFN?4. Overall, our data shows that the expression of distinct IFN? subtypes within the tumor microenvironment results in different anti-tumor activities, and differentially affects the efficacy of a cancer therapy targeting established disease.

SUBMITTER: Buzzai AC

PROVIDER: S-EPMC7145903 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Diverse Anti-Tumor Immune Potential Driven by Individual IFNα Subtypes.

Buzzai Anthony C AC Wagner Teagan T Audsley Katherine M KM Newnes Hannah V HV Barrett Lucy W LW Barnes Samantha S Wylie Ben C BC Stone Shane S McDonnell Alison A Fear Vanessa S VS Foley Bree B Waithman Jason J

Frontiers in immunology 20200403

Immunotherapies harnessing T cell immunity have shown remarkable clinical success for the management of cancer. However, only a proportion of patients benefit from these treatments. The presence of type I interferon (IFN) within the tumor microenvironment is critical for driving effective tumor-specific T cell immunity. Individuals can produce 12 distinct subtypes of IFNα, which all signal through a common receptor. Despite reported differences in anti-viral potencies, the concept that distinct ...[more]

PMID: 32308653

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Project description:The Type I Interferons (IFN-Is) are innate antiviral cytokines that include 12 different IFNα subtypes and IFNβ that signal through the IFN-I receptor (IFNAR), inducing hundreds of IFN-stimulated genes (ISGs) that comprise the 'interferome'. Quantitative differences in IFNAR binding correlate with antiviral activity, but whether IFN-Is exhibit qualitative differences remains controversial. Moreover, the IFN-I response is protective during acute HIV-1 infection, but likely pathogenic during the chronic stages. To gain a deeper understanding of the IFN-I response, we compared the interferomes of IFNα subtypes dominantly-expressed in HIV-1-exposed plasmacytoid dendritic cells (1, 2, 5, 8 and 14) and IFNβ in the earliest cellular targets of HIV-1 infection. Primary gut CD4 T cells from 3 donors were treated for 18 hours ex vivo with individual IFN-Is normalized for IFNAR signaling strength. Of 1,969 IFN-regulated genes, 246 'core ISGs' were induced by all IFN-Is tested. However, many IFN-regulated genes were not shared between the IFNα subtypes despite similar induction of canonical antiviral ISGs such as ISG15, RSAD2 and MX1, formally demonstrating qualitative differences between the IFNα subtypes. Notably, IFNβ induced a broader interferome than the individual IFNα subtypes. Since IFNβ, and not IFNα, is upregulated during chronic HIV-1 infection in the gut, we compared core ISGs and IFNβ-specific ISGs from colon pinch biopsies of HIV-1-uninfected (n = 13) versus age- and gender-matched, antiretroviral-therapy naïve persons with HIV-1 (PWH; n = 19). Core ISGs linked to inflammation, T cell activation and immune exhaustion were elevated in PWH, positively correlated with plasma lipopolysaccharide (LPS) levels and gut IFNβ levels, and negatively correlated with gut CD4 T cell frequencies. In sharp contrast, IFNβ-specific ISGs linked to protein translation and anti-inflammatory responses were significantly downregulated in PWH, negatively correlated with gut IFNβ and LPS, and positively correlated with plasma IL6 and gut CD4 T cell frequencies. Our findings reveal qualitative differences in interferome induction by diverse IFN-Is and suggest potential mechanisms for how IFNβ may drive HIV-1 pathogenesis in the gut.

Dataset Information

Diverse Anti-Tumor Immune Potential Driven by Individual IFN? Subtypes.

Publications

Diverse Anti-Tumor Immune Potential Driven by Individual IFNα Subtypes.

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