Abstract A022: Disrupting redox homeostasis initiates anti-tumor immune responses in pancreatic cancer
Notice bibliographique
Résumé
Abstract Although immune therapy has made impressive progress in cancer treatment, pancreatic ductal adenocarcinoma (PDAC) remains an exception, likely due to its immunosuppressive tumor microenvironment that prevents immune responses against the tumor. Our current work aims to reactivate the suppressive immune infiltrate using radiation therapy and oxidative stress to potentiate antitumor immune responses in PDAC. Our lab previously found that PDAC cells are dependent on the antioxidant peroxiredoxin-4 (PRDX4) expression. PRDX4 prevents excessive levels of reactive oxygen species in cells and while high PRDX4 expression is associated with a more aggressive disease, it is dispensable in normal tissue. As such, disrupting redox homeostasis by inhibiting PRDX4 represents a targetable vulnerability in cancer cells. To investigate the radio-sensitizing potential of PRDX4, we knocked-down (KD) PRDX4 in human pancreatic tumor cells as well as in mouse cancer cells obtained from the spontaneous KPC model (driven by the KRas and P53 mutations), in combination with radiation. Presence and quantification of DNA damage were performed by immunofluorescence, and impaired cell survival was analyzed by clonogenic assays. Changes in immune secretion were assessed by RT-qPCR and Elisa and in vitro macrophage phenotyping was performed upon exposure to tumor cell conditioned media. Our data so far show an accumulation of cytosolic DNA upon PRDX4 KD in PDAC cells, with the presence of micronuclei as well as less aggregated DNA. Interestingly, targeting PRDX4 before radiation amplifies the release of radiation-induced cytosolic DNA while significantly decreasing cell growth and survival, compared to radiation alone. Cytosolic DNA has been shown to trigger innate immune signaling in tumor cells. Consistently, PRDX4 loss induces the upregulation of many pro-inflammatory genes, including CCL5, CCL20, and CXCL10, in a STING-dependent manner. Combining PRDX4 KD with radiation leads to a higher gene upregulation of these immune stimulatory chemokines, as well as an increased protein secretion within tumor cell media. These findings support an amplified immunomodulatory effect of radiation when combined with PRDX4 loss in PDAC cells. To assess whether targeting PRDX4 can remodel the tumor microenvironment, we applied tumor conditioned media from cancer cells on isolated naive mouse CD45+/CD11c+/F4/80+ macrophages. Media from cells treated with PRDX4 KD + radiation strongly increased the migration ability of macrophages while modulating the expression of a subset of chemokine-encoding genes in immune cells. Using the spontaneous KPC model depleted for PRDX4, along with syngeneic orthotopic models, we are now aiming to confirm this radio-sensitizing and immune-modulatory potential of PRDX4 in vivo. The aggressiveness of PDAC requires research towards novel treatment strategies and our data strongly support evidence for targeting cancer metabolism, particularly antioxidant systems, in synergy with existing cancer therapies, like radiation and immune therapy. Citation Format: Lucie Malbeteau, Emily Poulton, Vishal Pandya, Marianne Koritzinsky. Disrupting redox homeostasis initiates anti-tumor immune responses in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A022.
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) | 0,002 | 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 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 ».