Identification of interleukin-13 receptor alpha2 peptide analogues capable of inducing improved antiglioma CTL responses.
Restricted and high-level expression of interleukin-13 receptor alpha2 (IL-13Ralpha2) in a majority of human malignant gliomas makes this protein an attractive vaccine target. We have previously described the identification of the IL-13Ralpha2(345-353) peptide as a human leukocyte antigen-A2 (HLA-A2)-restricted CTL epitope. However, as it remains unclear how efficiently peptide-based vaccines can induce specific CTLs in patients with malignant gliomas, we have examined whether analogue epitopes could elicit heteroclitic antitumor T-cell responses versus wild-type peptides. We have created three IL-13Ralpha2 analogue peptides by substitutions of the COOH-terminal isoleucine (I) for valine (V) and the NH(2)-terminal tryptophan (W) for either alanine (A), glutamic acid (E), or nonsubstituted (W; designated as 1A9V, 1E9V, and 9V, respectively). In comparison with the native IL-13Ralpha2 epitope, the analogue peptides 9V and 1A9V displayed higher levels of binding affinity and stability in HLA-A2 complexes and yielded an improved stimulatory index for patient-derived, specific CTLs against the native epitope expressed by HLA-A2(+) glioma cells. In HLA-A2-transgenic HHD mice, immunization with the peptides 9V and 1A9V induced enhanced levels of CTL reactivity and protective immunity against an intracranial challenge with IL13Ralpha2-expressing syngeneic tumors when compared with vaccines containing the native IL-13Ralpha2 epitope. These findings indicate highly immunogenic IL-13Ralpha2 peptide analogues may be useful for the development of vaccines capable of effectively expanding IL-13Ralpha2-specific, tumor-reactive CTLs in glioma patients.
Eguchi
Junichi
J
Department of Neurological Surgery, University of Pittsburgh School of Medicine, USA.
Hatano
Manabu
M
Nishimura
Fumihiko
F
Zhu
Xinmei
X
Dusak
Jill E
JE
Sato
Hidemitsu
H
Pollack
Ian F
IF
Storkus
Walter J
WJ
Okada
Hideho
H
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology; D045744:Cell Line, Tumor; D005910:Glioma / Q000276:immunology* / Q000628:therapy*; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D053661:Interleukin-13 Receptor alpha1 Subunit; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000276:immunology*; D053660:Receptors, Interleukin-13; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
D019496:Cancer Vaccines; D015789:HLA-A2 Antigen; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse; D053661:Interleukin-13 Receptor alpha1 Subunit; D010446:Peptide Fragments; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13