Identification of an HLA‐A*24:02‐restricted α‐fetoprotein signal peptide‐derived antigen and its specific T‐cell receptor for T‐cell immunotherapy

Abstract

Summary Hepatocellular carcinoma (HCC) is the most common type of liver cancer with limited treatments. Asia has the highest HCC incidence rates; China accounts for over 50% of all HCC cases worldwide. T‐cell receptor (TCR) ‐engineered T‐cell immunotherapies specific for human leukocyte antigen (HLA) ‐A*02:01‐restricted α‐fetoprotein (AFP) peptide have shown encouraging results in clinics. HLA‐A*24:02 is more common than HLA‐A*02:01 in Asian countries, including China. Here we identified a novel HLA‐A*24:02‐restricted peptide KWVESIFLIF (AFP2–11) located in AFP signal peptide domain by mass spectrometric analysis of HLA‐bound peptides from HepG2 cells. A TCR (KWV3.1) specific for AFP2–11‐HLA‐A*24:02 was isolated from peripheral blood mononuclear cells of a healthy donor. The binding affinity of soluble KWV3.1 to its antigen was determined to be ~55 μm, within the affinity range of native TCRs for self‐antigens. KWV3.1‐transfected T cells could specifically activate and kill AFP2–11 pulsed T2‐A24 cells and AFP+ HLA‐A*24:02+ tumor cell lines, demonstrating that AFP2–11 can be naturally presented on the surface of AFP+ tumor cell lines. The newly identified antigenic peptide can provide a novel target for immunotherapeutic strategies for patients with AFP+ HLA‐A*24:02+ HCC.

High-Throughput Sequencing-Based Analysis of T Cell Repertoire in Lupus Nephritis

“…Since a clinically important biomarker should predict which SLE individuals will develop LN later, subsequent research should make a comparison between SLE patients with and without LN. In addition, the human leukocyte antigen (HLA) gene profiles of the studied subjects are not assessed (24,25), which may restrict the generalizability of our results.…”

Natural Killer Cells and T Cells in Hepatocellular Carcinoma and Viral Hepatitis: Current Status and Perspectives for Future Immunotherapeutic Approaches

“…Importantly, these TCR gene engineered T cells could specifically kill HLA-A2 + AFP + HepG2 tumor cells, sparing normal hepatocytes in vitro [114]. AFP 2-11 -HLA-A*24:02 specific TCR transfected T cells could specifically activate and kill AFP 2-11 pulsed T2-A24 cells and AFP + HLA-A*24:02 + tumor cell lines, demonstrating that AFP 2-11 epitope can be naturally presented on the surface of AFP + tumor cell lines [115]. Antigens that are specific for HCC such as GPC3 and AFP are being tested as part of CAR constructs [116,117].…”

Cellular based immunotherapy for primary liver cancer

“…A-fetoprotein (AFP) specific CD8 + T cell clusters, deprived from human leukocyte antigen (HLA)-A2 transgenic AAD mice, were hybridized to generate CD8 + T cell with HLA-A2/AFP identifiable TCR, and the hybridoma T cell clones were detected to have effective toxicity on HCC tumor cells [ 66 ]. The immune therapeutic potency of HLA-2/AFP specific TCR against HCC was also confirmed with human peripheral blood mononuclear cell (PBMC) derived CD8 + T cells [ 67 ]. Further trials for AFP specific TCR T cells used on clinical therapy are underway (Table.…”