دورية أكاديمية
Arginase 1 is a key driver of immune suppression in pancreatic cancer
| العنوان: | Arginase 1 is a key driver of immune suppression in pancreatic cancer |
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| المؤلفون: | Rosa E Menjivar, Zeribe C Nwosu, Wenting Du, Katelyn L Donahue, Hanna S Hong, Carlos Espinoza, Kristee Brown, Ashley Velez-Delgado, Wei Yan, Fatima Lima, Allison Bischoff, Padma Kadiyala, Daniel Salas-Escabillas, Howard C Crawford, Filip Bednar, Eileen Carpenter, Yaqing Zhang, Christopher J Halbrook, Costas A Lyssiotis, Marina Pasca di Magliano |
| المصدر: | eLife, Vol 12 (2023) |
| بيانات النشر: | eLife Sciences Publications Ltd, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Medicine LCC:Science LCC:Biology (General) |
| مصطلحات موضوعية: | PDA, arginase, myeloid, CD8 T cells, immunosuppression, immunotherapy, Medicine, Science, Biology (General), QH301-705.5 |
| الوصف: | An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by the expression of the enzyme Arginase 1 (ARG1), which we demonstrated is potently expressed in pancreatic tumor-associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, ARG1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting arginine and inhibiting T cell activation. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2050-084X |
| Relation: | https://elifesciences.org/articles/80721; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.80721 |
| URL الوصول: | https://doaj.org/article/2b78244f89f74a1a8452e4521a5af646 |
| رقم الأكسشن: | edsdoj.2b78244f89f74a1a8452e4521a5af646 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 2050084X |
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| DOI: | 10.7554/eLife.80721 |