Identification of Aldo-Keto Reductase 1C3-derived Peptides Recognized by Cytotoxic T Cells in Hepatocellular Carcinoma Patients

Abstract

Aims: Identification of novel immunotherapy targets for hepatocellular carcinoma (HCC) is an urgent and important subject to improve the prognosis of patients. In the present study, using the data of complementary DNA (cDNA) microarray and immunological analyses, we identified aldo-keto reductase 1C3 (AKR1C3)-derived cytotoxic T cell (CTL) epitopes. Methods: The study included 54 HCC patients. The expression level of AKR1C3 in HCC and non-HCC liver tissue was examined by cDNA microarray, real-time polymerase chain reaction (PCR) and immunohistochemistry. Immune responses were measured by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) and CTL assays. Results: The expression level of AKR1C3 was higher in HCC tissue than in non-HCC liver tissue (p=0.013). In immunological assays, AKR1C3-derived peptides containing human leukocyte antigen (HLA)-A*2402 binding motifs and showing binding affinity to HLA-A*2402 induced CTLs to produce IFN-γ and kill an AKR1C3-producing hepatoma cell line. The frequency of AKR1C3-specific CTLs in peripheral blood mononuclear cells (PBMCs) was 10 to 23 per 3×10 5 PBMCs. The frequency of IFN-γ-producing AKR1C3-specific T cells in tumor-infiltrating lymphocytes (TILs) was higher than that in PBMCs, suggesting that AKR1C3-specific T cells infiltrate into the tumor and are functional. The analyses of the frequency of AKR1C3-specific CTLs before and after HCC treatments showed that AKR1C3-specific immune responses were enhanced by the treatments. Conclusions: We identified HLA-A*2402-restricted T cell epitopes derived from AKR1C3. The newly identified AKR1C3 epitopes could be a valuable component of HCC immunotherapy and for analyzing host immune responses to HCC. Immunogastroenterology 2012; 1:47-57