title: l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells.
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.
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Matthew
authors.initials: M
authors.lastname: Fletcher
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Ramirez
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Sierra
authors.affiliation: 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.
authors.forename: Patrick
authors.initials: P
authors.lastname: Raber
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Paul
authors.initials: P
authors.lastname: Thevenot
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Al-Khami
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Dulfary
authors.initials: D
authors.lastname: Sanchez-Pino
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Claudia
authors.initials: C
authors.lastname: Hernandez
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Dorota D
authors.initials: DD
authors.lastname: Wyczechowska
authors.affiliation: 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.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Ochoa
authors.affiliation: 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.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
mesh_terms: D000818:Animals; D001120:Arginine / Q000008:administration & dosage / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D004734:Energy Metabolism / Q000187:drug effects; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D011092:Polyethylene Glycols / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D011092:Polyethylene Glycols; D001120:Arginine