L-Arginine supplementation inhibits the growth of breast cancer by enhancing innate and adaptive immune responses mediated by suppression of MDSCs in vivo.
L-Arginine supplementation inhibits the growth of breast cancer by enhancing innate and adaptive immune responses mediated by suppression of MDSCs in vivo.
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DOI：
10.1186/s12885-016-2376-0
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发表时间：
2016-06-01
期刊：
影响因子：
3.8
通讯作者：
Jin F
中科院分区：
文献类型：
--
作者：
Cao Y;Feng Y;Zhang Y;Zhu X;Jin F
L-Arg参与许多生物学活动，包括T细胞的活化。在乳腺癌患者中，L-Arg被髓源性抑制细胞（MDSC）产生的一氧化氮合酶2（NOS 2）和精氨酸酶1（ARG-1）耗尽。我们的目的是测试是否补充L-Arg可以增强抗肿瘤免疫反应，提高乳腺肿瘤啮齿动物模型的生存率。测量对照和L-Arg处理的4只T1荷瘤（TB）BALB/c小鼠的肿瘤体积，并记录存活率。流式细胞术检测MDSC、树突状细胞（DCs）、调节性T细胞（Tcells）、巨噬细胞、CD 4 + T细胞和CD 8 + T细胞的百分比。另外，通过酶联免疫吸附试验（ELISA）测定IL-10、TNF-α和IFN-γ的水平，通过Griess反应测定一氧化氮（NO）水平。实时荧光定量RT-PCR检测IFN-γ、T-bet、Granzyme B、ARG-1和iNOSmRNA水平。L-Arg治疗可抑制肿瘤生长，延长4只T1 TB小鼠的存活时间。在L-Arg治疗的TB小鼠中，MDSC的频率被显着抑制。相反，巨噬细胞、CD 4 + T细胞和CD 8 + T细胞的数量和功能显著增强。脾细胞培养上清中IFN-γ、TNF-α、NO水平及脾细胞和瘤块中iNOS、IFN-γ、Granzyme B mRNA水平均显著升高。对肿瘤组织中ARG-1 mRNA水平、THP频率和IL-10水平无影响。补充L-Arg可显著抑制肿瘤生长，延长4只T1 TB小鼠的生存时间，这与MDSC减少有关，并增强了先天性和适应性免疫应答。
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.