64. Generation of Tumor Cells Resistant to Oncolysis Is Mediated Through Virus Induced APOBEC Expression
Notice bibliographique
Résumé
In both pre-clinical, and clinical models, we have observed that treatment of primary tumors with oncolytic viruses can lead to very significant tumor regressions, often with apparent disappearance of the tumor. However, in many cases, tumor subsequently recurs, often extremely aggressively. We have been able to mimic this effect in vitro by growing several different types of tumor cell lines in the presence of different oncolytic viruses at low m.o.i. over several weeks. Under such conditions, we consistently observe the emergence of cells which survive over long periods of time in culture, despite the demonstrable presence of ongoing viral replication. We identified APOBEC3 from a screen of genes which are induced in tumor cells undergoing continual exposure to either reovirus or Vesicular Stomatitis Virus (VSV). In this respect, overexpression of APOBEC3B, a cytidine deaminase, has been identified in human tumors associated with mutations that may drive tumorigenesis. Therefore, we tested the hypothesis that, upon infection with oncolytic viruses, APOBEC3 may help drive tumor cell mutation leading to protection from viral cytotoxicity. Consistent with this, both mRNA and protein levels of APOBEC3 were rapidly induced within 24-72 hours of low M.O.I infection by reovirus, or VSV, of B16 melanoma, GL261 glioma and TC2 prostate tumor murine cell lines. Similar low level infection of human tumor cell lines was associated with rapid induction of the human APOBEC3B mRNA. Interestingly, engineered over-expression of APOBEC3B in tumor lines significantly enhanced the ability of these cells to resist killing by either VSV or reovirus. This effect was inhibited by blockade of PKC signaling upon viral infection but was enhanced by the presence of type I interferons. Correspondingly, inhibition of APOBEC3 using shRNA decreased the frequency of emergence of VSV-resistant tumor populations. These data suggest that infection of tumor cells by oncolytic viruses at low M.O.I (as is likely to be the case during clinical treatments) leads to the induction of cellular proteins, which enhance the ability of resistance to oncolysis to develop. Deep sequencing studies are currently underway to determine the genetic changes in both virus, and target tumor cells, which are associated with APOBEC3 over-expression during chronic exposure to oncolytic virus infection. Finally, data will be presented on how these findings allow the construction of improved viruses for cancer therapy by targeting APOBEC3 induction to improve primary killing and prevent emergence of treatment resistant populations.
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Comment cette classification a été obtenuedéplier
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 | 0,000 | 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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 ».