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

Abstract

BACKGROUND & AIMS:

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 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 5-10×10(5) 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.

• Authors: Masafumi Shimoda, Yoshito Tomimaru, Kevin P Charpentier, Howard Safran, Rolf I Carlson, Jack Wands
• Journal: Journal of hepatology (J Hepatol) Vol. 56 Issue 5 Pg. 1129-1135 (May 2012) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 22245894 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Calcium-Binding Proteins
• Membrane Proteins
• Muscle Proteins
• Asph protein, mouse
• Mixed Function Oxygenases

Topics

• Animals
• CD4-Positive T-Lymphocytes (pathology)
• CD8-Positive T-Lymphocytes (pathology)
• Calcium-Binding Proteins (physiology)
• Carcinoma, Hepatocellular (pathology, physiopathology, therapy)
• Cell Line
• Dendritic Cells (pathology)
• Disease Models, Animal
• Disease Progression
• Female
• Humans
• Immunotherapy (methods)
• Leukocytes, Mononuclear (pathology)
• Liver Neoplasms (pathology, physiopathology, therapy)
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred BALB C
• Mixed Function Oxygenases (physiology)
• Muscle Proteins (physiology)
• Neoplasm Invasiveness (pathology)
• Neoplasm Recurrence, Local (prevention & control)