Identification of HLA-A2-restricted CTL epitopes of a novel tumour-associated antigen, KIF20A, overexpressed in pancreatic cancer

Abstract

Background:Identification of tumour-associated antigens (TAAs) that induce cytotoxic T lymphocytes (CTLs) specific to cancer cells is critical for the development of anticancer immunotherapy. In this study, we aimed at identifying a novel TAA of pancreatic cancer for immunotherapy.Methods:On the basis of the genome-wide cDNA microarray analysis, we focused on KIF20A (also known as RAB6KIFL/MKlp2) as a candidate TAA in pancreatic cancer cells. The HLA-A2 (A*02:01)-restricted CTL epitopes of KIF20A were identified using HLA-A2 transgenic mice (Tgm) and the peptides were examined to check whether they could generate human CTLs exhibiting cytotoxic responses against KIF20A+, HLA-A2+ tumour cells in vitro.Results:KIF20A was overexpressed in pancreatic cancer and in some other malignancies, but not in their non-cancerous counterparts and many normal adult tissues. We found that KIF20A-2 (p12–20, LLSDDDVVV), KIF20A-8 (p809–817, CIAEQYHTV), and KIF20A-28 (p284–293, AQPDTAPLPV) peptides could induce HLA-A2-restricted CTLs in HLA-A2 Tgm without causing autoimmunity. Peptide-reactive human CTLs were generated from peripheral blood mononuclear cells of HLA-A2+ healthy donors by in vitro stimulation with the three peptides, and those CTLs successfully exhibited cytotoxic responses to cancer cells expressing both KIF20A and HLA-A2.Conclusion:KIF20A is a novel promising candidate for anticancer immunotherapeutic target for pancreatic cancers.

Identification of Promiscuous KIF20A Long Peptides Bearing Both CD4+ and CD8+ T-cell Epitopes: KIF20A-Specific CD4+ T-cell Immunity in Patients with Malignant Tumor

“…Immunohistochemical staining of KIF20A using a rabbit polyclonal antibody against KIF20A (A300-879A, Bethyl Laboratories) was conducted as described previously (1,2,27 Peptide-stimulated degranulation of CD4 þ T lymphocytes was determined by flow cytometric analysis of CD107a exposed on the cell surface as described previously, with some modifications (28). Detailed methods are provided in Supplementary Materials and Methods.…”

“…KIF20A has been reported to be a promising immunotherapeutic target for cancers. Studies have reported that 2 short peptides (SP) derived from KIF20A, KIF20A-A2 , and KIF20A-A24 66-75 stimulated CTLs, which kill cancer cells endogenously expressing KIF20A antigen and that KIF20A-specific CTLs were present in peripheral blood mononuclear cells (PBMC) obtained from patients with pancreatic cancer (1,4). Phase I/II clinical trials of cancer immunotherapy for lung cancer, pancreatic cancer, and cholangiocellular carcinoma using KIF20A-derived SP are underway.…”

“…We recently used genome-wide cDNA microarray analysis to identify a novel tumor-associated antigen (TAA), kinesin family member 20A (KIF20A), which is frequently overexpressed in lung cancer, pancreatic cancer, gastric cancer, bladder cancer, breast cancer, melanoma, and various other malignancies (1)(2)(3). KIF20A has been reported to be a promising immunotherapeutic target for cancers.…”

Synaptonemal complex protein 3 is a prognostic marker in cervical cancer

“…CTAs are restricted in normal tissues to germ cells of the testis, with occasional expression in female reproductive organs, and are expressed in histologically different types of malignant human tumors [1][2][3][4]. The tumor restricted expression pattern of CTAs makes them an interesting target for immunotherapeutic approaches [3,5].…”

Identification and Validation of Targets for Cancer Immunotherapy: From the Bench-to-Bedside

“…SEREX was not limited to immunogenic cancers such as melanoma and has now been used to identify more than 2,000 antigens [22][23] in a large range of different solid [24][25][26] and haematological malignancies [27][28][29][30]. cDNA libraries are created from tumour samples, cell lines or healthy normal donor cells (such as testes).…”