Crisscross CTL induction by SYT-SSX junction peptide and its HLA-A*2402 anchor substitute.
To investigate the effects of anchor substitutions in SYT-SSX junction peptide, an HLA-A24 anchor residue (position 9) of the SYT-SSX B peptide (GYDQIMPKK) was substituted to more favorable residues according to the HLA-A24-binding motif. Among four substitutes constructed, a substitute with isoleucine (termed K9I peptide) most apparently enhanced the affinity for HLA-A24 molecule. Subsequent in vitro CTL induction analysis using PBMCs of 15 HLA-A24(+) synovial sarcoma patients revealed that the original B peptide allowed to induce synovial sarcoma-specific CTLs from 7 patients (47%), whereas such CTLs were inducible from 12 patients (80%) with K9I peptide. Moreover, the extent of cytotoxicity against HLA-A24(+) synovial sarcoma cell lines was higher in K9I peptide-induced CTLs than B peptide-induced CTLs. Influence of anchor substitution on peptide/TCR interaction was evaluated by cytotoxicity assays against autologous cells and tetramer analysis. CTLs induced from a synovial sarcoma patient using K9I peptide did not lyse autologous PHA blasts or EBV-infected B cells. In vitro stimulations of PBMCs from 5 HLA-A24(+) synovial sarcoma patients with K9I peptide increased the frequency of T cells reacting with both HLA-A24/K9I peptide tetramer and HLA-A24/B peptide tetramer. In contrast, the frequency of T cells reacting with HLA/HIV-derived peptide tetramer remained low. These findings support the validity in design of anchor residue substitution in SYT-SSX fusion gene-derived peptide, and provide a potential clue to the current stagnation in vaccination trials of fusion gene-derived natural junction peptides.
Ida
Kazunori
K
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Kawaguchi
Satoshi
S
Sato
Yuriko
Y
Tsukahara
Tomohide
T
Nabeta
Yuki
Y
Sahara
Hiroeki
H
Ikeda
Hideyuki
H
Torigoe
Toshihiko
T
Ichimiya
Shingo
S
Kamiguchi
Kenjiro
K
Wada
Takuro
T
Nagoya
Satoshi
S
Hiraga
Hiroaki
H
Kawai
Akira
A
Ishii
Takeshi
T
Araki
Nobuhito
N
Myoui
Akira
A
Matsumoto
Seiichi
S
Ozaki
Toshifumi
T
Yoshikawa
Hideki
H
Yamashita
Toshihiko
T
Sato
Noriyuki
N
D019943:Amino Acid Substitution; D015234:HLA-A Antigens / Q000276:immunology*; D059871:HLA-A24 Antigen; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000276:immunology*; D010455:Peptides / Q000276:immunology*; D013584:Sarcoma, Synovial / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015234:HLA-A Antigens; D059871:HLA-A24 Antigen; D015514:Oncogene Proteins, Fusion; D010455:Peptides; C116512:SYT-SSX fusion protein