HCA519/TPX2: a potential T-cell tumor-associated antigen for human hepatocellular carcinoma

Abstract

BackgroundImmunotherapy for human hepatocellular cancer (HCC) is slowly making progress towards treating these fatal cancers. The identification of new antigens can improve this approach. We describe a possible new antigen, hepatocellular carcinoma‐associated antigen‐519/targeting protein for Xklp‐2 (HCA519/TPX2), for HCC that might be beneficial for T‐cell specific HCC immunotherapy.MethodsHCC was studied for the expression for 15 tumor‐associated antigens considered useful for immunotherapy within three HCC cell lines (HepG2, Hep3B, and PLC/PRF/5), lymphocytes, non‐cancerous livers, and clinical HCC. The expression of tumor antigenic precursor proteins (TAPPs) messenger RNA was first screened by reverse transcriptase quantitative real‐time polymerase chain reaction.ResultsFour antigens (alpha fetoprotein, aspartyl/asparaginyl β­hydroxylase, glypican­3 and HCA519/TPX2) proved to be the best expressed TAPPs within the HCC specimens by molecular analyses. HCA519/TPX2 was detected by intracellular cell flow cytometry within HCC cell lines by using a specific antibody towards this TAPP. This antibody also detected the protein within primary HCCs. We synthesized two HCA519/TPX2 peptides (HCA519464–472 and HCA519351–359) which can bind to human leukocyte antigen (HLA)‐A*0201. Dendritic cells pulsed with these peptides stimulated cytolytic T lymphocytes (CTLs). These killer T‐cells lysed HLA‐A*0201+ T2 cells exogenously loaded with the correct specific peptide. The CTLs killed HepG2 (HLA‐A2+ and HCA519+), but not the Hep3B and PLC/PRF/5 cell lines, which are HCA519+ but HLA‐A2‐negative. In silico analysis reveals that HCA519/TPX2 has the inherent ability to bind to a very wide variety of HLA antigens.ConclusionHCA519/TPX2 is a viable immunotarget that should be further investigated within HCC patients.

The Immune System in Hepatocellular Carcinoma and Potential New Immunotherapeutic Strategies

“…A prerequisite for the successful development of T-cell-based immunotherapeutic approaches is the identification and characterization of immune responses to tumour-associated antigens (TAAs). Seven HCC-specific TAAs that are targeted by T cells have been identified: alpha-fetoprotein (AFP), glypican-3 (GPC3), NY-ESO-1, SSX-2, melanoma antigen gene-A (MAGE-A), telomerase reverse transcriptase (TERT) [ 27 – 31 ], hepatocellular carcinoma-associated antigen-519/targeting protein for Xklp-2 (HCA519/TPX2) [ 32 ].…”

Prognostic and clinical value of Targeting protein for Xenopus kinesin-like protein 2 in patients with gastrointestinal tract cancers

“…A study by Liu et al [23] showed that TPX2 might contribute to tumor cell invasion through activating AKT signaling and subsequently increasing MMP2 and MMP9 in HCC. [24] Takahashi et al [25] reported that the AURKA/TPX2 axis could drive colon tumorigenesis cooperatively with MYC and identified inhibiting AURKA/TPX2 axis could be a novel synthetic lethal therapeutic approach for MYC-driven cancers. TPX2 played an important role in promoting tumorigenesis and metastasis of human CC.…”

Emergence of immunotherapy as a novel way to treat hepatocellular carcinoma

“…Nevertheless, the clinical response to adoptive DC transfer is still not satisfactory, and, as a consequence, several measures have been devised to augment the efficacy of the adoptive DC transfer. Several groups proposed the priming of DC with other antigens, such as hepatocellular carcinoma-associated antigen-519/targeting protein for Xkl-2 (HCA519/TPX2)[ 59 ], epithelial cell adhesion molecule (EpCAM)[ 60 ], or ANAXA3[ 37 ]. Since EpCAM and ANAXA3 are selectively expressed in CSCs/CICs, the priming of DCs with these antigens may be effective to kill CSCs/CICs that are rather resistant to standard therapies such as chemotherapy and/or molecular targeted therapy.…”