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Priming with DNMT inhibitors potentiates PD-1 immunotherapy by triggering viral mimicry in relapsed/refractory NK/T-cell lymphoma

ABSTRACT: Priming with DNMT inhibitors potentiates PD-1 immunotherapy by triggering viral mimicry in relapsed/refractory NK/T-cell lymphoma

PROVIDER: PRJNA1237341 | ENA |

REPOSITORIES: ENA

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Priming with DNMT inhibitors potentiates PD-1 immunotherapy by triggering viral mimicry in relapsed/refractory NK/T-cell lymphoma

Project description:Anti-PD-1 immunotherapy has demonstrated significant anti-tumor efficacy in treating relapsed or refractory natural killer/T cell lymphoma (R/R NKTL). However, both intrinsic and acquired resistance remain a substantial challenge. DNA hypermethylation serves as a critical epigenetic modifier influencing anti-tumor immunity in NKTL. Here, we evaluate the efficacy and safety of combining DNA methyltransferase (DNMT) inhibitors with anti-PD-1 monoclonal antibody (mAb) as salvage therapy in 21 patients with R/R NKTL who had previously failed frontline immunotherapy. This combination therapy achieved an objective response rate (ORR) of 66.7% (14/21), with a complete response (CR) rate of 47.6% (10/21), and a 2-year overall survival (OS) rate of 50.2%. To investigate the mechanisms underlying the therapeutic efficacy of this combination, we established a preclinical xenograft model of acquired resistance to anti-PD-1 therapy. Our findings revealed that resistance to anti-PD-1 treatment was characterized by the absence of CD8+ T-cell infiltration and the inactivation of interferon pathways. In contrast, DNMT inhibitors restored CD8+ T-cell infiltration, and sensitized tumors to anti-PD-1 therapy. Mechanistically, DNMT inhibitors induced DNA demethylation of endogenous retroviral elements (ERVs), leading to the upregulation of endogenous nucleic acid expression and the activation of a viral mimicry response. This response subsequently triggered the type I interferon pathway, thereby enhancing anti-tumor immunity in both murine and human T-cell lymphoma models. Collectively, our study highlights the potential of DNMT inhibitors in restoring tumor sensitivity to anti-PD-1 therapy and provides compelling evidence for combining DNMT inhibitors with anti-PD-1 mAb as a promising therapeutic strategy for R/R NKTL.

2025-08-13 | GSE292179 | GEO

DNA methylation of Relapsed/Refractory AML

Project description:Genome wide DNA methylation profiling of blood and bone marrow of Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia. The Illumina Infinium EPIC Human DNA methylation Beadchip was used to obtain DNA methylation profiles across over 860,000 CpGs.

2023-12-31 | GSE225239 | GEO

Genomic Analysis of Relapsed/Refractory DLBCL

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Genomic Analysis of Relapsed/Refractory DLBCL

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DNA methylation of Relapsed/Refractory AML

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ViPOR in Relapsed/Refractory B-Cell Lymphoma

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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.

2024-08-08 | GSE268034 | GEO

Genomic profiling of relapsed and refractory childhood cancers

Project description:Genomic profiling of relapsed and refractory childhood cancers

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Genomic profiling of relapsed and refractory childhood cancers

Project description:Genomic profiling of relapsed and refractory childhood cancers

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Altered Expression Profiles of tRNA-derived fragments in relapsed/refractory multiple myeloma

Project description:tRNA related fragments(tRF) and tRNA halves(tiRNA) are novel class of short non-coding RNA derived from tRNAs. Using RNA sequencing, we evaluated the tRFs/tiRNAs expression profiles in relapsed/refractory multiple myeloma and multiple myeloma patients. Bioinformatics analyses indicated that tRFs/tiRNAs may be involved in the progression and drug-resistance of multiple myeloma.

2021-05-19 | GSE171003 | GEO

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