Inhibition of Aspartate β-Hydroxylase Enhances Anti-Tumor Immunity
Notice bibliographique
Résumé
Shweta Dilip Johari,1 Katerina Krausova,1 Barbora Zucha,1 Carlos Eduardo Madureira Trufen,2 Ingrid Polakova,1 Mark Olsen,3 Michal Smahel1 1Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, Vestec, Czech Republic; 2Czech Centre for Phenogenomics & Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic; 3Department of Pharmaceutical Sciences, College of Pharmacy – Glendale, Midwestern University, Glendale, AZ, USACorrespondence: Michal Smahel, Department of Genetics and Microbiology, Faculty of Science, Charles University, BIOCEV, Prumyslova 595, Vestec, 252 50, Czech Republic, Email smahelm@natur.cuni.czPurpose: Aspartate β-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 anti-metastatic 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. Keywords: cancer immunotherapy, ASPH, adaptive immunity, scRNA-seq, tumor microenvironment
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».