Tumor Progression-related Transmembrane Protein Aspartate-β-hydroxylase is a Target for Immunotherapy of Hepatocellular Carcinoma

Overview

Journal J Hepatol

Publisher Elsevier

Specialty Gastroenterology

Date 2012 Jan 17

PMID 22245894

Citations 30

Authors

Masafumi Shimoda

Yoshito Tomimaru

Kevin P Charpentier

Howard Safran

Rolf I Carlson

Jack Wands

Affiliations

Soon will be listed here.

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.

Citing Articles

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Aspartate β-Hydroxylase Serves as a Prognostic Biomarker for Neoadjuvant Chemotherapy in Gastric Cancer.

Gan X, Li S, Wang Y, Du H, Hu Y, Xing X Int J Mol Sci. 2023; 24(6).

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