ARM-X: an adaptable mesenchymal stromal cell-based vaccination platform suitable for solid tumors
Notice bibliographique
Résumé
In addition to triggering endosomal escape, the Accum® platform was recently reported for its ability to instill antigen cross-presentation properties in mesenchymal stromal cells (MSCs). Despite the promising results obtained with the first-generation vaccine using the A1 Accum® derivative (ARM vaccine), large quantities of cancer antigens were required to achieve meaningful therapeutic effects. Given this limitation, additional Accum® variants were engineered and tested for their ability to lower the need for large antigen quantities. A leading variant, AccuTOX®, was selected for that purpose. Several functional studies, including a series of antigen cross-presentation assays, were conducted using the SIINFEKL-specific T-cell clone B3Z. Analysis of endosomal escape and the effect of various anti-oxidant compounds were used to decipher the AccuTOX® mode of action in MSCs. The potency of the AccuTOX®-reprogramed MSCs (ARM-X) cells was evaluated in the context of therapeutic vaccination using immunocompetent C57BL/6 mice with three different pre-established solid tumor models. Various depletion studies were also conducted in animals to identify effector cells involved in the therapeutic response mediated by the ARM-X cells. Finally, the effect observed on murine ARM-X cells was validated on human MSCs along with an immunopeptidome study reflecting the cross-presentation potency of these reprogrammed human cells. AccuTOX® can indeed trigger MSCs to cross-present antigens, even if pulsed with low doses of tumor antigens while retaining most of the innate properties of A1, including increased antigen uptake and processing, production of reactive oxygen species, endosomal escape and induction of the unfolded protein response (UPR). When tested against melanoma, pancreatic and colon cancer, therapeutic administration of the ARM-X vaccine, in combination with anti-PD-1, impairs tumor growth. Mechanistically, the ARM-X vaccine relies on efferocytosis by endogenous phagocytes and requires both CD4+ and CD8+ T cells, as their depletion leads to a loss in therapeutic function. Altogether, this second-generation ARM-X vaccine represents a platform adaptable to multiple solid tumors. In addition, our data clearly allude to a direct link between AccuTOX®-mediated UPR activation and antigen cross-presentation by MSCs. The fact that these modulated MSCs become antigen-presenting cells via UPR stimulation opens-up a new line of investigation to search for additional agents capable of specifically activating this pathway to convert culture-adapted MSCs to a cellular vaccination tool adaptable to various cancer indications.
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Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,003 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
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 tête enseignante, 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 ».