精氨酸酶
免疫系统
癌症研究
胰腺癌
生物
CD8型
巨噬细胞极化
T细胞
免疫疗法
肿瘤微环境
细胞毒性T细胞
基因剔除小鼠
细胞生物学
巨噬细胞
免疫学
癌症
精氨酸
受体
生物化学
遗传学
氨基酸
体外
作者
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 C. Bischoff,Padma Kadiyala,Daniel J. Salas-Escabillas,Howard C. Crawford,Filip Bednar,Eileen S. Carpenter,Yaqing Zhang,Christopher J. Halbrook,Costas A. Lyssiotis,Marina Pasca di Magliano
出处
期刊:eLife
[eLife Sciences Publications, Ltd.]
日期:2023-02-02
卷期号:12
被引量:22
摘要
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.
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