Dataset Information

Combining ERAP1 silencing and entinostat therapy to overcome resistance to cancer immunotherapy in neuroblastoma

ABSTRACT: Checkpoint immunotherapy unleashes tumor control by T cells, but it is undermined in non-immunogenic tumors, e.g. with low MHC class I expression and low neoantigen burden, such as neuroblastoma (NB). Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides before loading on MHC class I molecules. Inhibition of ERAP1 results in the generation of new antigens able of inducing potent anti-tumor immune responses. Here, we identify a novel non-toxic combinatorial strategy based on genetic inhibition of ERAP1 and administration of the HDAC inhibitor (HDACi) entinostat that increase the immunogenicity of NB, making it responsive to PD-1 therapy.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Fibroblast

DISEASE(S): Neuroblastoma

SUBMITTER: Kirti Pandey

LAB HEAD: Anthony Wayne Purcell

PROVIDER: PXD055268 | Pride | 2025-05-07

REPOSITORIES: Pride

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			Action	DRS
	20240812_KP_AC_DF_9464D_CondA_2814_S1-A1_1_4850.d.zip	Other
	20240812_KP_AC_DF_9464D_CondA_2814_S1-A1_1_4850.mgf	Mgf
	20240812_KP_AC_DF_9464D_CondA_2814_S1-A1_1_4850.raw.mgf	Mgf
	20240812_KP_AC_DF_9464D_CondA_Y3_S1-A5_1_4854.d.zip	Other
	20240812_KP_AC_DF_9464D_CondA_Y3_S1-A5_1_4854.mgf	Mgf

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Combining ERAP1 silencing and entinostat therapy to overcome resistance to cancer immunotherapy in neuroblastoma.

Tempora Patrizia P D'Amico Silvia S Gragera Paula P Damiani Verena V Krol Kamila K Scaldaferri Valentina V Pandey Kirti K Chung Shanzou S Lucarini Valeria V Giorda Ezio E Scarsella Marco M Volpe Gabriele G Pezzullo Marco M De Stefanis Cristiano C D'Oria Valentina V De Angelis Lorenzo L Giovannoni Roberto R De Ioris Maria Antonietta MA Melaiu Ombretta O Purcell Anthony W AW Locatelli Franco F Fruci Doriana D

Journal of experimental & clinical cancer research : CR 20241022 1

<h4>Background</h4>Checkpoint immunotherapy unleashes tumor control by T cells, but it is undermined in non-immunogenic tumors, e.g. with low MHC class I expression and low neoantigen burden, such as neuroblastoma (NB). Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that trims peptides before loading on MHC class I molecules. Inhibition of ERAP1 results in the generation of new antigens able of inducing potent anti-tumor immune responses. Here, we identify a novel non-toxic combinat ...[more]

PMID: 39438988

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Project description:Ulcerative colitis (UC) is a life-threatening heterogeneous condition characterized by inflammation of the colon. Endoplasmic reticulum aminopeptidase 1 (ERAP1) is essential for antigen processing and immune regulation, however, its specific role in UC pathogenesis and therapeutic response remains unclear. This study aimed to investigate the role of ERAP1 in the response to sulfasalazine, a standard treatment for UC, using an ERAP1-heterozygous (ERAP1⁺/⁻) mouse model susceptible to colitis. Wild-type (WT) and ERAP1+/− mice were treated with 2.5% dextran sulfate sodium (DSS) to induce colitis, followed by sulfasalazine administration. Colitis severity was assessed through histopathology. Immune cell populations, including neutrophils, dendritic cells, T cells, and NK1.1+ cells, were analyzed using flow cytometry. RNA sequencing of colonic tissues was performed to assess gene expression changes associated with reduced ERAP1 expression. ERAP1+/− mice exhibited more severe DSS-induced colitis, with greater weight loss and increased mucosal damage compared to WT mice. In addition, ERAP1+/− colitis mice showed marked changes in peripheral blood and intestinal intraepithelial lymphocyte (IELs) immune cell infiltration after sulfasalazine treatment. RNA sequencing identified 428 differentially expressed genes between ERAP1⁺/⁻ and WT mice. Among these, 28 genes were previously associated with colitis or colorectal cancer, of which 11 were upregulated and 17 downregulated in ERAP1⁺/⁻ mice. RT-qPCR analysis further confirmed that the expression of Anxa9, Atp2a1, and Hepacam2 was significantly elevated in ERAP1⁺/⁻ mice following sulfasalazine treatment, suggesting a differential therapeutic response. Collectively, our study demonstrates that partial ERAP1 deficiency exacerbates DSS-induced colitis by promoting immune dysregulation and altering the expression of inflammation-related genes. These findings suggest that reduced ERAP1 expression may impair the therapeutic efficacy of sulfasalazine. Therefore, ERAP1 may serve as a key regulator in the pathogenesis of UC and a potential target for therapy.