title: L-Arginine supplementation inhibits the growth of breast cancer by enhancing innate and adaptive immune responses mediated by suppression of MDSCs in vivo.
abstract: L-Arg is involved in many biological activities, including the activation of T cells. In breast cancer patients, L-Arg is depleted by nitric oxide synthase 2 (NOS2) and arginase 1 (ARG-1) produced by myeloid-derived suppressor cells (MDSCs). Our aim was to test whether L-Arg supplementation could enhance antitumor immune response and improve survivorship in a rodent model of mammary tumor.
  
  
  
  Tumor volumes in control and L-Arg treated 4 T1 tumor bearing (TB) BALB/c mice were measured and survival rates were recorded. The percentages of MDSCs, dendritic cells (DCs), regulatory T cells (Tregs), macrophages, CD4(+) T cells, and CD8(+) T cells were examined by flow cytometry. Additionally, levels of IL-10, TNF-α, and IFN-γ were measured by enzyme-linked immunosorbent assay (ELISA) and nitric oxide (NO) levels were measured by the Griess reaction. IFN-γ, T-bet, Granzyme B, ARG-1 and iNOS mRNA levels were examined by real-time RT-PCR.
  
  
  
  L-Arg treatment inhibited tumor growth and prolonged the survival time of 4 T1 TB mice. The frequency of MDSCs was significantly suppressed in L-Arg treated TB mice. In contrast, the numbers and function of macrophages, CD4(+) T cells, and CD8(+) T cells were significantly enhanced. The IFN-γ, TNF-α, NO levels in splenocytes supernatant, as well as iNOS, IFN-γ, Granzyme B mRNA levels in splenocytes and tumor blocks were significantly increased. The ARG-1 mRNA level in tumor blocks, the frequency of Tregs, and IL-10 level were not affected.
  
  
  
  L-Arg supplementation significantly inhibited tumor growth and prolonged the survival time of 4 T1 TB mice, which was associated with the reduction of MDSCs, and enhanced innate and adaptive immune responses.
authors.affiliation: Department of Surgical Oncology and Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Laboratory Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Medical Examination Center, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, 110122, China.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Surgical Oncology and Breast Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, China. jinfeng66cn@hotmail.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D001120:Arginine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D001120:Arginine
keywords: Breast cancer; L-Arginine; MDSCs; Tumor immunity