L-Arginine supplementation inhibits the growth of breast cancer by enhancing innate and adaptive immune responses mediated by suppression of MDSCs in vivo

Abstract

BackgroundL-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.MethodsTumor 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.ResultsL-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.ConclusionL-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.

Effect of amino-acid intake on physical conditions and skin state: a randomized, double-blind, placebo-controlled, crossover trial

“…This result may be explained by the effect of multi vitamins as suggested by Boyera et al (37) L-Arginine plays the central role in several biological systems including immune functions (6) and the intake of L-arginineenriched supplement enhanced the potency of self-antitumor immunity, prolonged survival time, and inhibited the growth of tumor in a cancer model mouse by inhibiting the number of myeloid-derived suppressor cells. (38) L-Arginine is a substrate of both arginase and nitric oxide synthase (NOS) and is converted to urea and L-ornithine by arginase and to NO by NOS. L-Ornithine is a precursor of L-proline and important in the growth and restoration of cells.…”

Metabolism in cancer metastasis: bioenergetics, biosynthesis, and beyond

“…NO mediates T‐cell suppression by interfering with T‐cell JAK/STAT signaling, inhibiting expression of the major histocompatibility complex (MHC) proteins, and inducing T‐cell apoptosis . These two different arginine‐associated pathways of immunosuppression make it difficult to predict the effect of arginine supplementation, which may rescue the arginine deficiency of T cells and inhibit tumor growth, or alternatively inhibit T‐cell function by stimulating NO production . In addition, arginine may directly promote the growth of arginine‐dependent tumor cells .…”

Myeloid derived suppressor cells contribute to the malignant progression of oral squamous cell carcinoma

“…Namdar et al [50] showed that Foxp3 vaccination suppressed MDSCs activity via a significant decrease of Arg-1 and iNOS to reduction of melanoma growth in a murine model. Cao et al [51] demonstrated that L-Arg supplementation significantly inhibited tumor growth by reduction of MDSCs, and enhanced innate and adaptive immune responses in melanoma mice model. Hence, we tested the expression of iNOS and Arg-1 in PBMCs after cocultures with OSCC, and found OSCC could enhance the levels of iNOS and Arg-1, providing evidence that tumor cells could educate the immune cells to immunosuppressive phenotype.…”