TY - JOUR
T1 - Crisscross CTL induction by SYT-SSX junction peptide and its HLA-A*2402 anchor substitute
AU - Ida, Kazunori
AU - Kawaguchi, Satoshi
AU - Sato, Yuriko
AU - Tsukahara, Tomohide
AU - Nabeta, Yuki
AU - Sahara, Hiroeki
AU - Ikeda, Hideyuki
AU - Torigoe, Toshihiko
AU - Ichimiya, Shingo
AU - Kamiguchi, Kenjiro
AU - Wada, Takuro
AU - Nagoya, Satoshi
AU - Hiraga, Hiroaki
AU - Kawai, Akira
AU - Ishii, Takeshi
AU - Araki, Nobuhito
AU - Myoui, Akira
AU - Matsumoto, Seiichi
AU - Ozaki, Toshifumi
AU - Yoshikawa, Hideki
AU - Yamashita, Toshihiko
AU - Sato, Noriyuki
PY - 2004/7/15
Y1 - 2004/7/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.173.2.1436
DO - 10.4049/jimmunol.173.2.1436
M3 - Article
C2 - 15240740
AN - SCOPUS:3142700682
VL - 173
SP - 1436
EP - 1443
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -