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Chronic viral mimicry induction following p53 loss promotes immune evasion [Mouse RNASeq]

ABSTRACT: Chronic viral mimicry induction following p53 loss promotes immune evasion [Mouse RNASeq]

PROVIDER: PRJNA896208 | ENA |

REPOSITORIES: ENA

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Chronic viral mimicry induction following p53 loss promotes immune evasion

Project description:Chronic viral mimicry induction following p53 loss promotes immune evasion

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Chronic viral mimicry induction following p53 loss promotes immune evasion [Mouse RNASeq]

Project description:Epigenetic therapies that alter DNA- and/or histone modifications facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events that include functional inactivation of canonical tumor suppressor proteins also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize patient-derived premalignant lesions of the fallopian tube along with syngeneic mouse models of epithelial ovarian cancer to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss disrupts constitutive heterochromatin to permit transcription of immunogenic repetitive elements capable of activating viral mimicry responses. While acute viral mimicry activation diminishes cell fitness, chronic viral mimicry activation following p53 loss promotes epigenetic reprogramming that increases tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity as a pro-survival adaptation. This selection process we describe as ‘viral mimicry conditioning’ can be partially attenuated by the reverse transcriptase inhibitor 3TC to delay spontaneous tumorigenesis. Altogether, these results reveal that viral mimicry conditioning following p53 loss selects for diminished cell immunogenicity to promote immune evasion upon cancer initiation. Disruption of viral mimicry conditioning during cancer initiation may represent a pharmacological target for early cancer interception.

2024-03-26 | GSE216639 | GEO

Chronic viral mimicry induction following p53 loss promotes immune evasion

Project description:This SuperSeries is composed of the SubSeries listed below.

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Project description:While pancreatic ductal adenocarcinomas (PDAC) are addicted to KRAS-activating mutations, inhibitors of downstream effectors in the KRAS pathway, such as the clinically approved MEK1/2 kinases inhibitor Trametinib, are devoid of significant therapeutic effects. Nevertheless, the extensive rewiring of regulatory circuits driven by the attenuation of the KRAS pathway can induce novel functional states and vulnerabilities of potential therapeutic relevance. An in-depth molecular analysis of the transcriptional and epigenomic alterations occurring in PDAC cells in the initial hours after MEK1/2 inhibition by Trametinib, unveiled a massive induction of a large number of retroelements, in particular endogenous retroviruses (ERVs), that in these cells escaped epigenetic silencing. In turn, the increased abundance of ERV-derived double stranded RNAs induced a strong Interferon (IFN) response. Pathway deconvolution allowed us to track ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated non-silenced retroelements and synergized with IRF1 (Interferon regulatory factor 1) in the activation of interferons and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the design of combination therapies in immuno-oncology.

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Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer [ChIP-seq]

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Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation

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GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma

Project description:Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.

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