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      l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells.

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          Abstract

          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 in vitro. Moreover, serum levels of citrulline increased after in vivo administration of peg-Arg I. In support of the hypothesis that peg-Arg I acted indirectly to block T-cell responses in vivo, 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.

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          Author and article information

          Journal
          Cancer Res.
          Cancer research
          1538-7445
          0008-5472
          Jan 15 2015
          : 75
          : 2
          Affiliations
          [1 ] Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
          [2 ] Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
          [3 ] Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
          [4 ] Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana. Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana. prodri1@lsuhsc.edu.
          Article
          0008-5472.CAN-14-1491 NIHMS644449
          10.1158/0008-5472.CAN-14-1491
          25406192
          361e18ae-64f4-4e7e-92ef-0aea660e078f
          ©2014 American Association for Cancer Research.
          History

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