Tumor progression-related transmembrane protein aspartate-β-hydroxylase is a target for immunotherapy of hepatocellular carcinoma.
Tumor progression-related transmembrane protein aspartate-β-hydroxylase is a target for immunotherapy of hepatocellular carcinoma.
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DOI：
10.1016/j.jhep.2011.12.016
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发表时间：
2012-05
影响因子：
25.7
通讯作者：
Wands, Jack
中科院分区：
文献类型：
--
作者：
Shimoda, Masafumi;Tomimaru, Yoshito;Charpentier, Kevin P.;Safran, Howard;Carlson, Rolf I.;Wands, Jack
肝细胞癌（HCC）由于经常性肝内转移和缺乏有效的辅助治疗，生存率很低。天冬氨酸-β-羟化酶（ASPH）是一种有吸引力的细胞靶点，因为它是在鼠和人HCC肿瘤上过表达的高度保守的跨膜蛋白，并且促进以增强的肿瘤细胞迁移和侵袭为特征的恶性表型。将从脾脏扩增和分离的树突状细胞（DC）与细胞因子混合物一起孵育以优化IL-12分泌和共刺激分子表达，然后随后加载ASPH蛋白用于免疫。采用预防性和治疗性实验方法，向小鼠注射同基因BNL HCC肿瘤细胞，然后皮下接种5-10×105 ASPH负载的DC。肿瘤浸润淋巴细胞（TIL）的特点，并确定其在产生抗肿瘤作用的作用。还探索了ASPH蛋白相对于来自人外周血单核细胞（PBMC）的活化抗原特异性CD 4 + T细胞的免疫原性。我们发现，免疫治疗与ASPH负载的DC抑制和延迟建立HCC和肿瘤生长时，给药化疗。体外再刺激实验和体内耗竭研究表明，CD 4+和CD 8+细胞均有助于抗肿瘤作用。使用来自健康志愿者和HCC患者的PBMC，我们发现ASPH刺激导致抗原特异性CD 4 + T细胞的显着发育。ASPH负载的DC免疫具有显著的抗肿瘤作用，可以降低HCC复发的风险。
Hepatocellular carcinoma (HCC) has a poor survival rate due to recurrent intrahepatic metastases and lack of effective adjuvant therapy. Aspartate-β-hydroxylase (ASPH) is an attractive cellular target since it is a highly conserved transmembrane protein overexpressed on both murine and human HCC tumors, and promotes a malignant phenotype as characterized by enhanced tumor cell migration and invasion. Dendritic cells (DCs), expanded and isolated from the spleen, were incubated with a cytokine cocktail to optimize IL-12 secretion and co-stimulatory molecule expression, then subsequently loaded with ASPH protein for immunization. Mice were injected with syngeneic BNL HCC tumor cells followed by subcutaneous inoculation with 5–10×105 ASPH loaded DCs using a prophylactic and therapeutic experimental approach. Tumor infiltrating lymphocytes (TILs) were characterized, and their role in producing anti-tumor effects determined. The immunogenicity of ASPH protein with respect to activating antigen specific CD4+ T cells derived from human peripheral blood mononuclear cells (PBMCs) was also explored. We found that immunotherapy with ASPH-loaded DCs suppressed and delayed established HCC and tumor growth when administered prophylactically. Ex-vivo re-stimulation experiments and in vivo depletion studies demonstrate that both CD4+ and CD8+ cells contributed to anti-tumor effects. Using PBMCs derived from healthy volunteers and HCC patients, we showed that ASPH stimulation led to significant development of antigen-specific CD4+ T-cells. Immunization with ASPH-loaded DCs has substantial anti-tumor effects which could reduce the risk of HCC recurrence.
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DOI：
10.1084/jem.188.12.2357
发表时间：
1998-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hung K;Hayashi R;Lafond-Walker A;Lowenstein C;Pardoll D;Levitsky H
通讯作者：
Levitsky H
影响因子：
13.5
作者：
Longato, Lisa;de la Monte, Suzanne;Kuzushita, Noriyoshi;Horimoto, Masayoshi;Rogers, Arlin B.;Slagle, Betty L.;Wands, Jack R.
通讯作者：
Wands, Jack R.
影响因子：
15.9
作者：
Lavaissiere, L;Jia, S;Friedman, PA
通讯作者：
Friedman, PA
影响因子：
4.4
作者：
Bricard, G;Bouzourene, H;Speiser, DE
通讯作者：
Speiser, DE
影响因子：
3.9
作者：
Lee, WC;Wang, HC;Chen, MF
通讯作者：
Chen, MF