抑制器
精氨酸
髓源性抑制细胞
细胞生物学
化学
髓样
细胞
癌症研究
生物
生物化学
基因
氨基酸
作者
Matthew L. M. Fletcher,Marcos Ramírez,Rosa A. Sierra,Patrick Raber,Paul Thevenot,Amir A. Al-Khami,Dulfary Sanchez-Pino,C Hernández,Dorota Wyczechowska,Augusto C. Ochoa,Paulo C. Rodríguez
标识
DOI:10.1158/0008-5472.c.6507398
摘要
<div>Abstract<p>Enzymatic depletion of the nonessential amino acid l-Arginine (l-Arg) in patients with cancer by the administration of a pegylated form of the catabolic enzyme arginase I (peg-Arg I) has shown some promise as a therapeutic approach. However, l-Arg deprivation also suppresses T-cell responses in tumors. In this study, we sought to reconcile these observations by conducting a detailed analysis of the effects of peg-Arg I on normal T cells. Strikingly, we found that peg-Arg I blocked proliferation and cell-cycle progression in normal activated T cells without triggering apoptosis or blunting T-cell activation. These effects were associated with an inhibition of aerobic glycolysis in activated T cells, but not with significant alterations in mitochondrial oxidative respiration, which thereby regulated survival of T cells exposed to peg-Arg I. Further mechanistic investigations showed that the addition of citrulline, a metabolic precursor for l-Arg, rescued the antiproliferative effects of peg-Arg I on T cells <i>in vitro</i>. Moreover, serum levels of citrulline increased after <i>in vivo</i> administration of peg-Arg I. In support of the hypothesis that peg-Arg I acted indirectly to block T-cell responses <i>in vivo</i>, peg-Arg I inhibited T-cell proliferation in mice by inducing accumulation of myeloid-derived suppressor cells (MDSC). MDSC induction by peg-Arg I occurred through the general control nonrepressed-2 eIF2α kinase. Moreover, we found that peg-Arg I enhanced the growth of tumors in mice in a manner that correlated with higher MDSC numbers. Taken together, our results highlight the risks of the l-Arg–depleting therapy for cancer treatment and suggest a need for cotargeting MDSC in such therapeutic settings. <i>Cancer Res; 75(2); 275–83. ©2014 AACR.</i></p></div>
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