Targeted Inflammation During Oncolytic Virus Therapy Severely Compromises Tumor Blood Flow
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Notice bibliographique
Résumé
Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumor lysis by viral infection, we observed that a significant portion of the in vivo tumor killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumor cells. Shortly after administering the oncolytic virus we observed limited virus infection, coincident with a loss of blood flow to the interior of the tumor that correlated with induction of apoptosis in tumor cells. Transcript profiling of tumors showed that virus infection resulted in a dramatic transcriptional activation of pro-inflammatory genes including the neutrophil chemoattractants CXCL1 and CXCL5. Immunohistochemical examination of infected tumors revealed infiltration by neutrophils correlating with chemokine induction. Depletion of neutrophils in animals prior to VSV administration eliminated uninfected tumor cell apoptosis and permitted more extensive replication and spreading of the virus throughout the tumor. Taken all together, these results indicate that targeted recruitment of neutrophils to infected tumor beds enhances the killing of malignant cells. We propose that activation of inflammatory cells can be used for enhancing the effectiveness of oncolytic virus therapeutics, and that this approach should influence the planning of therapeutic doses. Oncolytic viruses (OVs) are selected or designed to eliminate malignancies by direct infection and lysis of cancer cells. In contrast to this concept of direct tumor lysis by viral infection, we observed that a significant portion of the in vivo tumor killing activity of two OVs, vesicular stomatitis virus (VSV) and vaccinia virus is caused by indirect killing of uninfected tumor cells. Shortly after administering the oncolytic virus we observed limited virus infection, coincident with a loss of blood flow to the interior of the tumor that correlated with induction of apoptosis in tumor cells. Transcript profiling of tumors showed that virus infection resulted in a dramatic transcriptional activation of pro-inflammatory genes including the neutrophil chemoattractants CXCL1 and CXCL5. Immunohistochemical examination of infected tumors revealed infiltration by neutrophils correlating with chemokine induction. Depletion of neutrophils in animals prior to VSV administration eliminated uninfected tumor cell apoptosis and permitted more extensive replication and spreading of the virus throughout the tumor. Taken all together, these results indicate that targeted recruitment of neutrophils to infected tumor beds enhances the killing of malignant cells. We propose that activation of inflammatory cells can be used for enhancing the effectiveness of oncolytic virus therapeutics, and that this approach should influence the planning of therapeutic doses.
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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 | 0,001 | 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 | 0,001 | 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 découle