Abstract A134: The immunoregulatory enzyme IDO induces resistance to common chemotherapy drugs via base excision repair pathway
Notice bibliographique
Résumé
Abstract Indoleamine 2,3-dioxygenase-1 (IDO) is an immune-regulatory enzyme expressed by most human tumors. IDO expression by tumor cells and the cells of the tumor microenvironment induces anergy and apoptosis in tumor-infiltrating NK cells, CD4+ and CD8+ T cells. IDO-mediated immune suppression is a major obstacle to successful immunotherapy. IDO levels are correlated with increased metastasis and poor patient outcome in many hematological and solid tumors. There is ample evidence that shows IDO induces resistance to ipilimumab and hinders its effectiveness against melanoma. We have recently shown that IDO induces resistance to the PARP inhibitor olaparib, ionizing radiation, and cisplatin independent of its immune-evading functions. However, our knowledge is limited about tumor cell-autonomous effects of IDO that are independent of its well known roles in regulating and suppressing anti-tumor immune responses. We therefore sought to study the underlying mechanism involved in IDO-mediated drug resistance. IFNγ was used to induce IDO in human lung adenocarcinoma A549 cells. Most cancer cells also express IDO in vivo in response to IFNγ production from immune cells. Clonal populations of A549 cells stably-transfected with anti-IDO shRNA or scrambled control shRNA were used to study IDO effects on drug sensitivity and resistance. We show, for the first time, that IDO mediates human tumor cell resistance to NAD+ inhibitor FK866, base excision repair (BER) inhibitor methoxyamine (MX), folate anti-metabolite pemetrexed, nucleoside analogue gemcitabine, and combined treatment with pemetrexed and MX, in the absence of immune cells. Concurrent knock-down of IDO and thymidylate synthase (TS), a key rate-limiting enzyme in DNA synthesis and repair, sensitizes human lung cancer cells to drugs that are commonly used in clinic, pemetrexed and 5FUdR. Based on the differential response of cancer cells to the different drugs we used in this study, we conclude that BER in IDO-expressing A549 cells plays a major role in inducing resistance to the drugs mentioned above. IDO inhibitors are under clinical trial mostly to improve the immune response towards cancer cells in patients. Our findings underlie the central role that IDO plays in not only suppressing the anti-tumor immune response but also causing resistance to common chemotherapeutics. Debulking the tumor and eradicating the immune-suppressive environment surrounding the tumor by pretreating patients with chemotherapy and radiation before immunotherapy could increase the chance of success for the latter. However, IDO could reduce the effectiveness of the treatment and therefore targeting IDO should be considered in studies that combine conventional chemotherapy with immunotherapy. Citation Format: Saman Maleki Vareki, Chen Di, Christine Di Cresce, Peter J. Ferguson, Mark Vincent, Weiping Min, Xiufen Zheng, James Koropatnick. The immunoregulatory enzyme IDO induces resistance to common chemotherapy drugs via base excision repair pathway. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A134.
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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 | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,001 | 0,002 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,002 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 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 ».