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Long noncoding RNA INCA1 regulates tumor interferon signaling

ABSTRACT: Tumor interferon signaling regulates the expression of immunosuppressive molecules and promotes cancer immune evasion. Although the role of long noncoding RNAs (lncRNAs) in the regulation of gene expression is now emerging, their function in tumor interferon signaling remains unexplored. We have identified the interferon-γ (IFNγ)-stimulated non-coding RNA 1 (INCA1) as a novel lncRNA expressed form the PD-L1 locus. INCA1 is expressed in multiple tumor types and its levels increase after IFNγ stimulation. In this study we performed transcriptome analysis (RNA-seq) of INCA1 knockdown cells and show that INCA1 regulates the expression of several interferon-stimulated genes. Overall, our findings reveal INCA1 as a critical component of the tumor interferon signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137454 | GEO | 2020/07/29

REPOSITORIES: GEO

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Project description:Ocular immune privilege (IP) limits immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber (a.c.) of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized immune mechanisms responsible for spontaneous rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. Microarray data showed a 3-fold increase in interferon (IFN)-γ and a 2.7-fold increase in Fas ligand (FasL). There was a robust increase in transcripts (127 of 408 surveyed) from interferon (IFN)-stimulated genes and a marked decrease (in 40 of 192 surveyed) in the expression of cell-cycle-associated genes. Non-microarray data confirmed that IFNγ, FasL and CD8+ T cells but not perforin or TNFα were required for elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthsis). IFNγ and FasL did not target tumor cells directly as the majority of SPLNX IFNγR1-/- mice and Fas-defective lpr mice failed to eliminate ocular E.G7-OVA tumors that expressed Fas and IFNγR1. Bone marrow chimeras showed that immune cell expression of IFNγR1 and Fas was critical and that SPLNX increased the frequency of activated macrophages within ocular tumors in an IFNγ- and Fas/FasL-dependent manner. Rejection of intraocular tumors was associated with increased ocular mRNA expression of several inflammatory genes including FasL, NOS2, CXCL2 and T-bet. Our data support a model in which IFNγ- and Fas/FasL-dependent activation of intratumoral macrophage by CD8+ T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis. The immunosuppressive mechanisms which maintain ocular IP likely interfere with the interaction between CD8+ T cells and macrophage to limit immunosurveillance of intraocular tumors. C57BL/6 mice that were splenectomized (Tumor_splnx) or were not surgically manipulated (Tumor_intact) were challenged with 10^4 luciferase-expressing E.G7-OVA cells injected into the anterior chamber of the eye. Fifteen days later, the animals were euthanized and tumor-bearing eyes were removed.

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Long noncoding RNA INCA1 regulates tumor interferon signaling

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