Abstract 3788: Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer
Notice bibliographique
Résumé
Abstract Introduction New therapeutic interventions are essential for improved management of patients with metastatic colorectal cancer (mCRC). This is especially critical for patients whose tumors harbor a mutation in the KRAS oncogene (40-45%). This patient cohort is excluded from receiving anti-EGFR monoclonal antibodies that have added a significant therapeutic benefit for KRAS wild type CRC patients. Reovirus, a dsRNA virus is in clinical development for patients with chemotherapy refractory KRAS mutated tumors. We hypothesize that effective expression of host Toll Like Receptors 3 (TLR3) will dampen the infection potential of reovirus propagation by mounting an innate immune response. Development of strategies to mitigate the TLR3 response pathway can be utilized as a tool towards improved virus productivity to specifically target the KRAS mutated cancer cells. Methodology: TLR3 expressing HEK293 cells were treated with reovirus to confirm that TLR 3 is the host pattern recognition motif of the host cellular machinery that is responsible for the detection of dsRNA harboring reovirus. TLR 3 was next down regulated by shRNA technology in KRAS mutated HCT116 CRC cell line and treated with reovirus at dose of 5 MOI (multiplicity of infection) for 48 hours. The cell proliferation profile under this treatment condition was measured by MTT assay and corelated with the proliferation pattern of TLR3 expressing HCT116 cells undergoing similar treatment. Cytokine ELISA was performed for interferon (INF) alpha (α)and beta (β) to determine the downstream consequences of the gene silencing. Finally xenograft tumor models of athymic nude mice (Foxn1nu) were developed with TLR3 silenced HCT116 cells and treated with reovirus at a daily intra tumoral (IT) dose of 1×107 TCID (tissue culture infective dose) and compared to tumors generated by HCT116 cells receiving identical treatment. Results ¬ TLR 3 is confirmed to be the host pattern recognition motif for dsRNA containing reovirus ¬ TLR3 which is constitutively expressed by colon epithelium is also a mediator of virus recognition in CRC cell line HCT116. ¬ Down regulation of TLR3 by shRNA technology enhances viral propagation as measured by MTT assay. ¬ Cytokine ELISA assay of INF α β distinctly reveals that downstream activation post reovirus infection is compromised. ¬ In xenograft models, those of TLR3 down regulated HCT116 cells, showed improved control of tumor growth with reovirus treatment as compared to those with TLR 3 expressing HCT 116 cells (p = 0.04) Conclusion TLR3 plays an important role in recognition of reovirus and mounting an innate immune response by inducing the secretion of type I INF. Mitigation of the TLR3 receptor mediated pattern recognition by shRNA down regulates host immune response and thus improves virus mediated cell cytotoxicity. The findings can be therapeutically utilized towards improved and beneficial killing of cancer cells by reovirus. Citation Format: Radhashree Maitra, Titto Augustine, Matt Coffey, Sanjay Goel. Toll like receptor 3 as an immunotherapeutic target for KRAS mutated colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3788.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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) | 0,004 | 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 ».