Tumor progression-related transmembrane protein aspartate-尾-hydroxylase is a target for immunotherapy of hepatocellular carcinoma

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• 作者：Masafumi Shimoda¹ ; ^&dagger ; ; Yoshito Tomimaru¹ ; Kevin P. Charpentier² ; Howard Safran³ ; Rolf I. Carlson¹ ; Jack Wands¹ ; ³ ; ^{jack_wands_md@brown.edu}
• 关键词：HCC ; hepatocellular carcinoma ; ASPH ; aspartate-尾-hydroxylase ; DCs ; dendritic cells ; TILs ; tumor infiltrating lymphocytes ; PBMCs ; peripheral blood mononuclear cells ; HBV ; hepatitis B ; HCV ; hepatitis C ; CTLs ; cytotoxic T lymphocytes ; TAAs ; tumor-associated
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：May, 2012
• 卷：56
• 期：5
• 页码：1129-1135
• 文件大小：1232 K

摘要

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Background & Aims

Hepatocellular carcinoma (HCC) has a poor survival rate due to recurrent intrahepatic metastases and lack of effective adjuvant therapy. Aspartate-尾-hydroxylase (ASPH) is an attractive cellular target since it is a highly conserved transmembrane protein overexpressed in both murine and human HCC tumors, and promotes a malignant phenotype as characterized by enhanced tumor cell migration and invasion.

Methods

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 脳 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.

Results

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 demonstrated 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.

Conclusions

Immunization with ASPH-loaded DCs has substantial anti-tumor effects which could reduce the risk of HCC recurrence.