Modulation of the functions of myeloid-derived suppressor cells : a new strategy of hydrogen sulfide anti-cancer effects.
- 作者列表："De Cicco P","Ercolano G","Rubino V","Terrazzano G","Ruggiero G","Cirino G","Ianaro A
BACKGROUND AND PURPOSE:Myeloid-derived suppressor cells (MDSCs) represent a major obstacle to cancer treatment, as they negatively regulate anti-tumour immunity through the suppression of tumour-specific T lymphocytes. Thus, the efficacy of immunotherapies may be improved by targeting MDSCs. In this study, we assessed the ability of hydrogen sulfide (H2 S), a gasotransmitter whose anti-cancer effects are well known, to inhibit the accumulation and immunosuppressive functions of MDSCs in melanoma. EXPERIMENTAL APPROACH:Effects of H2 S on the host immune response to cancer were evaluated using an in vivo syngeneic model of murine melanoma. B16F10-melanoma-bearing mice were treated with the H2 S donor, diallyl trisulfide (DATS) and analysed for content of MDSCs, dendritic cells (DCs) and T cells. Effects of H2 S on expression of immunosuppressive genes in MDSCs and on T cell proliferation were evaluated. KEY RESULTS:In melanoma-bearing mice, DATS inhibited tumour growth, and this effect was associated with a reduction in the frequency of MDSCs in the spleen, in the blood as well as in the tumour micro-environment. In addition, we found that CD8+ T cells and DCs were increased. Furthermore, DATS reduced the immuno-suppressive activity of MDSCs, restoring T cell proliferation. CONCLUSIONS AND IMPLICATIONS:The H2 S donor compound, DATS, inhibited the expansion and the suppressive functions of MDSCs, suggesting a novel role for H2 S as a modulator of MDSCs in cancer. Therefore, H2 S donors may provide a novel approach for enhancing the efficacy of melanoma immunotherapy. LINKED ARTICLES:This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.
背景和目的: 髓源性抑制细胞 (MDSCs) 是癌症治疗的主要障碍，因为它们通过抑制肿瘤特异性 T 淋巴细胞负调节抗肿瘤免疫。因此，免疫疗法的疗效可以通过靶向 MDSCs 来改善。在这项研究中，我们评估了硫化氢 (H2 S) 的能力，这是一种众所周知的 gasotransmitter，其抗癌作用抑制 MDSCs 在黑色素瘤中的积累和免疫抑制功能。 实验方法: 使用小鼠黑色素瘤的体内同基因模型评价 H2 S 对宿主对癌症免疫应答的影响。用 H2 S 供体二烯丙基三硫 (DATS) 处理 B16F10-melanoma-bearing 小鼠，分析 MDSCs 、树突状细胞 (DCs) 和 T 细胞的含量。评价 H2 S 对 MDSCs 免疫抑制基因表达和 T 细胞增殖的影响。 关键结果: 在荷黑色素瘤小鼠中，DATS 抑制肿瘤生长，这种作用与脾脏中 MDSCs 频率的降低相关, 在血液以及肿瘤微环境中。此外，我们发现 CD8 + T 细胞和 DCs 增加。此外，DATS 降低了 MDSCs 的免疫抑制活性，恢复了 T 细胞增殖。 结论和意义: H2 S 供体化合物 DATS 抑制 MDSCs 的扩增和抑制功能，提示 H2 S 作为 MDSCs 的调节剂在癌症中的新作用。因此，H2 S 供体可能为增强黑色素瘤免疫治疗的疗效提供一种新的方法。 链接文章: 本文是生物与医学中硫化氢主题部分的一部分。要查看本节中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/ 10.1111/bph.v177.4/issuetoc。
METHODS::In colorectal cancer (CRC), hepatic arterial infusion (HAI) chemotherapy may convert primarily unresectable CRC liver metastases (CLM) into resectability, although the risk of metastatic recurrence remains high after CLM ablation. We investigated the role of antitumour immunity invoked by first-line oxaliplatin-HAI for long-term CLM outcome. In a prospective study cohort of primarily unresectable CLM, we assessed patients' fms-related tyrosine kinase 3 ligand (FLT3LG) in serum, reflecting opportune intratumoural immune activity, at baseline and following 1-3 sequences of oxaliplatin-HAI. The end points were CLM resectability and overall survival. Patients who presented an immediate twofold increment of circulating FLT3LG during the treatment and at its completion were scored as CLM resectable (16.4% with both features), were alive at final follow-up 8-12 years later. All patients experienced FLT3LG increase during the treatment course, but those who remained unresectable or had the disease converted but presented a slow and gradual FLT3LG accretion, later died of the metastatic disease. These data provide further support to our previous findings that tumour-directed immunity invoked by oxaliplatin-containing therapy predicts excellent outcome of early advanced CRC if macroscopic tumour ablation is rendered possible by the 'classic' tumour response to the cytotoxic treatment.
METHODS::Prostate cancer is one of the primary causes of death around the world. As an important drug, flutamide has been used in the clinical diagnosis of prostate cancer. However, the over dosage and improper discharge of flutamide could affect the living organism. Thus, it necessary to develop the sensor for detection of flutamide with highly sensitivity. In this paper, we report the synthesis of lanthanum cobaltite decorated halloysite nanotube (LCO/HNT) nanocomposite prepared by a facile method and evaluated for selective reduction of flutamide. The as-prepared LCO/HNT nanocomposite shows the best catalytic performance towards detection of flutamide, when compared to other bare and modified electrodes. The good electrochemical performance of the LCO/HNT nanocomposite modified electrode is ascribed to abundant active sites, large specific surface area and their synergetic effects. Furthermore, the LCO/HNT modified electrode exhibits low detection limit (0.002 μM), wide working range (0.009-145 μM) and excellent selectivity with remarkable stability. Meaningfully, the developed electrochemical sensor was applied in real environmental samples with an acceptable recovery range.
METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.