Abstract PO-085: Inhibition of ATR as a therapeutic strategy to enhance immunotherapy in head and neck cancer
Notice bibliographique
Résumé
Abstract Background: Immunotherapy has become a new standard in the care of patients with head and neck squamous cell carcinoma (HNSCC). A number of patients’ tumors do not respond to this treatment, and recent studies have established an immunomodulatory role for the ATR-CHK1 signaling axis in the tumor microenvironment and the specific effects of ATR inhibitors in stimulating an innate immune response. Therefore, we have assessed the efficacy of the novel ATR inhibitor (AZD6738) as monotherapy and in combination with anti-PD-1 antibody in a syngeneic mouse model of HNSCC. Methods: In vitro clonogenic survival assays were used to evaluate the IC50 values of the ATR inhibitor AZD6738 in syngeneic MOC1, MOC2 and ROC1 mouse HNSCC cell lines. Western blotting and ATR shRNA knock-down strategies were performed to examine drug specificity and dissect molecular mechanisms. An orthotopic syngeneic mouse model of head and neck cancer was used to explore in vivo efficacy of the combination treatment. Immune profiling on tumor tissues obtained following drug treatment was assessed by immunohistochemistry and multiplex immunofluorescence analyses. Conditioned medium (CM) and bone marrow (BM) cells were obtained and subjected to flow cytometric analyses to assess myeloid cell phenotypic and functional markers. Coculture of the BM cells with mouse splenic T cells was also conducted to measure suppression of T cell activation and proliferation. Results: MOC1, MOC2 and ROC1 cell lines treated in vitro with various concentrations of single agent AZD6738 showed an IC50 value of 0.18-0.625 µmol/L. Combination of AZD3867 and anti-PD-1 antibody significantly reduced tumor growth and prolonged survival in mice injected with MOC1 cells orthotopically in the oral tongue compared to control and other treatment groups (P <0.0001 and P = 0.001, respectively). Combination therapy was well-tolerated and no weight loss was observed in mice. The CD4+T, CD8+ T lymphocytes and NK cells were elevated in mice tumors treated with combination of the drug compared to other treatment groups. Additionally, the inhibitory FoxP3+ Treg cells were significantly reduced (P = 0007) in mice tumors following the combination treatment. The BM cells exposed to CM collected from ATR shRNA MOC1/2 cell lines, and those treated ex-vivo with AZD6738 alone demonstrated decreased arginase-1 expression and a reduced capacity to inhibit T cell activation and proliferation relative to control groups. These findings suggest a role for ATR in modulating myeloid derived suppressive cell (MDSC) function. Mechanistically, we demonstrated that the ATR inhibition caused DNA damage response leading to cGAS/STING pathway activation associated with decreased STAT3 phosphorylation in vitro and in vivo in syngeneic head and neck cancer cells. Conclusion: In this study, we demonstrate that the immunogenic effects of AZD6738 are mediated by cytotoxic T cells as well as innate immunity. The combination of AZD6738 and anti-PD-1 warrants further exploration as a novel combination therapy for HNSCC. Citation Format: Abdullah A. Osman, Fabio H. B. da Costa, Adewale A. Adebayo, Mason D. Bartels, Tongxin Xie, Moran Amit, Mutsuki Kawabe, Roberto Rangel, Mitchell J. Frederick, Vlad Sandulache, Andrew G. Sikora, Jeffrey N. Myers. Inhibition of ATR as a therapeutic strategy to enhance immunotherapy in head and neck cancer [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PO-085.
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) | 0,003 | 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 ».