Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice.
Nanoliposome C6-Ceramide Increases the Anti-tumor Immune Response and Slows Growth of Liver Tumors in Mice.
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DOI：
10.1053/j.gastro.2017.10.050
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发表时间：
2018-03
期刊：
影响因子：
29.4
通讯作者：
Staveley-O'Carroll KF
中科院分区：
文献类型：
--
作者：
Li G;Liu D;Kimchi ET;Kaifi JT;Qi X;Manjunath Y;Liu X;Deering T;Avella DM;Fox T;Rockey DC;Schell TD;Kester M;Staveley-O'Carroll KF
神经酰胺是一种鞘脂代谢物，影响T细胞信号传导，诱导癌细胞凋亡，并减缓小鼠肿瘤生长。然而，由于其在水溶液中的细胞不渗透性和沉淀，它还没有被用作化学治疗剂。我们开发了一种纳米脂质体负载的C6-ceremide（LipC 6）来克服这一限制，并研究了其在小鼠肝肿瘤中的作用。免疫活性C57 BL/6小鼠腹腔注射四氯化碳和脾内注射致癌肝细胞。结果，类似于人类肝细胞癌的肿瘤在纤维化肝脏环境中发展。肿瘤形成后，每隔一天通过尾静脉向小鼠注射LipC 6或载体，持续2周。随后也通过尾静脉给予从系416小鼠脾脏分离的肿瘤抗原特异性（TAS）CD 8 + T细胞，随后通过腹膜内注射表达肿瘤抗原的B6/WT-19细胞进行免疫。用磁共振成像监测肿瘤生长。采用免疫组化和免疫印迹分析肿瘤细胞凋亡、增殖和AKT表达。采用流式细胞术、实时聚合酶链反应（PCR）和ELISA研究TAS CD 8 + T细胞和肿瘤相关巨噬细胞（TAM）的细胞因子产生、表型和功能。采用荧光法检测集落刺激因子2（GMCSF或CSF 2）或集落刺激因子1（MCSF或CSF 1）诱导的TAM和骨髓源性巨噬细胞中的活性氧（ROS）。与载体相比，注射LipC 6通过减少肿瘤细胞增殖和AKT的磷酸化以及增加肿瘤细胞凋亡来减缓肿瘤生长。与给予溶媒、LipC 6、T细胞或单独免疫的小鼠相比，给予LipC 6注射和TAS CD 8 + T细胞联合免疫的小鼠中肿瘤生长更慢。LipC 6注射也减少了TAM的数量及其ROS的产生。LipC 6诱导TAM分化为M1表型，这降低了免疫抑制并增加了CD 8 + T细胞的活性。这些结果通过用GMCSF或MCSF诱导的骨髓源性巨噬细胞的实验来验证。在患有肝肿瘤的小鼠中，注射LipC 6减少了TAM的数量和TAM抑制抗肿瘤免疫应答的能力。LipC 6还增加TAS CD 8 + T细胞的抗肿瘤作用。因此，LipC 6可能会增加肝癌患者免疫治疗的疗效。
Ceramide, a sphingolipid metabolite, affects T-cell signaling, induces apoptosis of cancer cells, and slows tumor growth in mice. However, it has not been used as a chemotherapeutic agent because of its cell impermeability and precipitation in aqueous solution. We developed a nanoliposome-loaded C6-ceremide (LipC6) to overcome this limitation and investigated its effects in mice with liver tumors. Immune competent C57BL/6 mice received intraperitoneal injections of carbon tetrachlo-ride and intra-splenic injections of oncogenic hepatocytes. As a result, tumors resembling human hepatocellular carcinomas developed in a fibrotic liver setting. After tumors formed, mice were given an injection of LipC6 or vehicle via tail vein every other day for 2 weeks. This was followed by administration, also via tail vein, of tumor antigen-specific (TAS) CD8+ T cells isolated from the spleens of line 416 mice, and subsequent immunization by intraperitoneal injection of tumor antigen-expressing B6/WT-19 cells. Tumor growth was monitored with magnetic resonance imaging. Tumor apoptosis, proliferation, and AKT expression were analyzed using immunohistochemistry and immunoblots. Cytokine production, phenotype, and function of TAS CD8+ T cells and tumor-associated macrophages (TAMs) were studied with flow cytometry, real-time polymerase chain reaction (PCR), and ELISA. Reactive oxygen species (ROS) in TAMs and bone marrow-derived macrophages, induced by colony stimulating factor 2 (GMCSF or CSF2) or colony stimulating factor 1 (MCSF or CSF1), were detected using a luminescent assay. Injection of LipC6 slowed tumor growth by reducing tumor cell proliferation and phosphorylation of AKT, and increasing tumor cell apoptosis, compared with vehicle. Tumors grew more slowly in mice given the combination of LipC6 injection and TAS CD8+ T cells followed by immunization compared with mice given vehicle, LipC6, the T cells, or immunization alone. LipC6 injection also reduced numbers of TAMs and their production of ROS. LipC6 induced TAMs to differentiate into an M1 phenotype, which reduced immune suppression and increased activity of CD8+ T cells. These results were validated by experiments with bone marrow-derived macrophages induced by GMCSF or MCSF. In mice with liver tumors, injection of LipC6 reduces the number of TAMs and the ability of TAMs to suppress the anti-tumor immune response. LipC6 also increases the anti-tumor effects of TAS CD8+ T cells. LipC6 might therefore increase the efficacy of immune therapy in patients with hepatocellular carcinoma.
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DOI：
10.1097/ppo.0b013e3181eb5066
发表时间：
2010-07
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
--
作者：
Emens LA
通讯作者：
Emens LA
影响因子：
13.5
作者：
Avella, Diego M.;Li, Guangfu;Schell, Todd D.;Liu, Dai;Zhang, Samuel Shao-Min;Lou, Xi;Berg, Arthur;Kimchi, Eric T.;Tagaram, Hephzibah Rani S.;Yang, Qing;Shereef, Serene;Garcia, Luis S.;Kester, Mark;Isom, Harriet C.;Rountree, C. Bart;Staveley-O'Carroll, Kevin F.
通讯作者：
Staveley-O'Carroll, Kevin F.
影响因子：
25.7
作者：
Li G;Liu D;Cooper TK;Kimchi ET;Qi X;Avella DM;Li N;Yang QX;Kester M;Rountree CB;Kaifi JT;Cole DJ;Rockey DC;Schell TD;Staveley-O'Carroll KF
通讯作者：
Staveley-O'Carroll KF
影响因子：
4.4
作者：
Martinez, Fernando O.;Gordon, Siamon;Mantovani, Alberto
通讯作者：
Mantovani, Alberto
影响因子：
20.3
作者：
Duluc, Dorothee;Delneste, Yves;Jeannin, Pascale
通讯作者：
Jeannin, Pascale