Identification of Lck-derived peptides applicable to anti-cancer vaccine for patients with human leukocyte antigen-A3 supertype alleles

M Naito,A Yamada,T Shirakusa,M Harada,Y Ishihara,M Noguchi,Y Komohara,K Itoh,Y Yamashita

doi:10.1038/sj.bjc.6604071

Abstract

The identification of peptide vaccine candidates to date has been focused on human leukocyte antigen (HLA)-A2 and -A24 alleles. In this study, we attempted to identify cytotoxic T lymphocyte (CTL)-directed Lck-derived peptides applicable to HLA-A11+, -A31+, or -A33+ cancer patients, because these HLA-A alleles share binding motifs, designated HLA-A3 supertype alleles, and because the Lck is preferentially expressed in metastatic cancer. Twenty-one Lck-derived peptides were prepared based on the binding motif to the HLA-A3 supertype alleles. They were first screened for their recognisability by immunoglobulin G (IgG) in the plasma of prostate cancer patients, and the selected candidates were subsequently tested for their potential to induce peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A3 supertype+ cancer patients. As a result, four Lck peptides were frequently recognised by IgGs, and three of them – Lck90−99, Lck449−458, and Lck450−458 – efficiently induced peptide-specific and cancer-reactive CTLs. Their cytotoxicity towards cancer cells was mainly ascribed to HLA class I-restricted and peptide-specific CD8+ T cells. These results indicate that these three Lck peptides are applicable to HLA-A3 supertype+ cancer patients, especially those with metastasis. This information could facilitate the development of peptide-based anti-cancer vaccine for patients with alleles other than HLA-A2 and -A24.

Highlights

53% of Chinese, 46% of Japanese, and 43% of North American African Americans and Hispanics were positive for the human leukocyte antigen (HLA)-A3 supertype alleles (Sette and Sidney, 1999)
The Lck protein is known to be essential for both T-cell development and function (Veillette et al, 1989), this protein is aberrantly expressed in several malignancies, including colon carcinoma, small cell lung carcinoma, and prostate carcinoma with a trend of preferential expression in metastatic lesions (Robinson et al, 1996; McCracken et al, 1997; Krystal et al, 1998; Lutz et al, 1998)
Thereafter, we carried out peptide-based immunotherapy against various types of cancer in which Lck-derived peptides were vaccinated into HLA-A24 þ or -A2 þ cancer patients (Sato et al, 2003; Mine et al, 2004)

Summary

Introduction

53% of Chinese, 46% of Japanese, and 43% of North American African Americans and Hispanics were positive for the HLA-A3 supertype alleles (Sette and Sidney, 1999). Biological roles of the Lck protein in cancer cells have not been fully confirmed, several lines of evidence suggest that this protein contributes to the process of neoplastic transformation (Marth et al, 1988; Robinson et al, 1996; McCracken et al, 1997; Krystal et al, 1998; Lutz et al, 1998) In support of this idea, several studies have reported that the Lck protein may contribute to the anchorage-independent growth of TGF-b-initiated tumour cells through the transcription of p56lck with a type I promoter (Amundadottir and Leder, 1998). We further attempted to identify novel Lck-derived peptide candidates that would be applicable to cancer patients with HLA-A3 supertype alleles to expand the possibilities of a peptide-based vaccine for metastatic cancer patients with alleles other than HLA-A2 and -A24

Objectives

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Conclusion