Introduction of a point mutation into an HLA class I single-chain trimer induces enhancement of CTL priming and antitumor immunity

Masanori Matsui; Masaaki Kawano; Sho Matsushita; Toshitaka Akatsuka

doi:10.1038/mtm.2014.27

Introduction of a point mutation into an HLA class I single-chain trimer induces enhancement of CTL priming and antitumor immunity

Mol Ther Methods Clin Dev. 2014 Jul 2:1:14027. doi: 10.1038/mtm.2014.27. eCollection 2014.

Authors

Masanori Matsui¹, Masaaki Kawano², Sho Matsushita³, Toshitaka Akatsuka¹

Affiliations

¹ Department of Microbiology, Saitama Medical University , Iruma-gun, Saitama, Japan.
² Department of Allergy and Immunology, Saitama Medical University , Iruma-gun, Saitama, Japan.
³ Department of Allergy and Immunology, Saitama Medical University , Iruma-gun, Saitama, Japan ; Allergy Center, Saitama Medical University , Iruma-gun, Saitama, Japan.

Abstract

We previously discovered one particular HLA-A*02:01 mutant that enhanced peptide-specific cytotoxic T lymphocyte (CTL) recognition in vitro compared to wild-type HLA-A*02:01. This mutant contains a single amino acid substitution from histidine to leucine at position 74 (H74L) that is located in the peptide-binding groove. To investigate the effect of the H74L mutation on the in vivo CTL priming, we took advantage of the technology of the HLA class I single-chain trimer (SCT) in which three components involving a peptide, β2 microglobulin and the HLA class I heavy chain are joined together via flexible linkers. We generated recombinant adenovirus expressing SCT comprised influenza A matrix protein (FMP)-derived peptide, β2 microglobulin and the H74L heavy chain. HLA-A*02:01 transgenic mice were immunized with the adenovirus, and the induction of peptide-specific CTLs and antitumor immunity was investigated. It was clearly shown that the H74L mutation enabled the HLA-A*02:01 SCT molecule to dramatically enhance both in vivo priming of FMP-specific CTLs and protection against a lethal challenge of tumor cells expressing FMP. These data present the first evidence that a simple point mutation in the HLA class I heavy chain of SCT is beneficial for improving CTL-based immunotherapy and prophylaxis to control tumors.