Inhibition of Aspartate β-Hydroxylase Enhances Anti-Tumor Immunity

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F25%3A00645662" target="_blank" >RIV/68378050:_____/25:00645662 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11310/25:10499506

Result on the web

<a href="https://doi.org/10.2147/ITT.S530987" target="_blank" >https://doi.org/10.2147/ITT.S530987</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.2147/ITT.S530987" target="_blank" >10.2147/ITT.S530987</a>

Result language

angličtina

Original language name

Inhibition of Aspartate β-Hydroxylase Enhances Anti-Tumor Immunity

Original language description

Purpose: Aspartate (3-hydroxylase (ASPH) contributes to carcinogenesis by promoting tumor cell proliferation, migration, and invasion. The enzymatic activity of ASPH can be inhibited by small molecule inhibitors that have been shown to have antimetastatic activity in rodent models. ASPH has also been shown to inhibit the activation of natural killer (NK) cells. Therefore, this study aimed to investigate the effect of ASPH inhibition on the induction of anti-tumor immunity and to analyze the immune cells involved. Methods: In the mouse TC-1/A9 model characterized by reversible downregulation of major histocompatibility class I (MHC-I) molecules, ASPH inhibition was combined with stimulation of innate and/or adaptive immunity, and the anti-tumor response was analyzed by evaluation of tumor growth, in vivo depletion of immune cell subpopulations, and ELISPOT assay. Characteristics of immune cells in the spleen and tumor were determined by flow cytometry and single-cell RNA sequencing (scRNA-seq). Results: ASPH inhibition did not reduce tumor growth or promote the anti-tumor effect of innate immunity stimulation with the synthetic oligonucleotide ODN1826, but it significantly enhanced tumor growth reduction induced by DNA vaccination. In vivo immune cell depletion suggested that CD8+ T cells played a critical role in this immunity stimulated by combined treatment with ASPH inhibition and DNA vaccination. ASPH inhibition also significantly enhanced the specific response of CD8+ T cells induced by DNA vaccination in splenocytes, as detected by ELISPOT assay, and reduced the number of regulatory T cells in tumors. scRNA-seq confirmed the improved activation of CD8+ T cells in tumor-infiltrating cells after combined therapy with DNA vaccination and ASPH inhibition. It also showed activation of NK cells, macrophages, and dendritic cells in tumors. Conclusion: ASPH inhibition stimulated T-cell-mediated adaptive immunity induced by DNA vaccination. Different types of lymphoid and myeloid cells were likely involved in the activated immune response that was efficient against tumors with MHC-I downregulation, which are often resistant to T-cell-based therapies. Due to different types of activated immune cells, ASPH inhibition could improve immunotherapy for tumors with various MHC-I expression levels.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

ImmunoTargets and Therapy

ISSN

2253-1556

e-ISSN

2253-1556

Volume of the periodical

14

Issue of the periodical within the volume

7 Jul

Country of publishing house

NZ - NEW ZEALAND

Number of pages

22

Pages from-to

697-718

UT code for WoS article

001526770200001

EID of the result in the Scopus database

2-s2.0-105010961650