CTLs directed against HER2 specifically cross-react with HER3 and HER4.
The human epidermal growth factor receptor 2 (HER2) has been targeted as a breast cancer-associated Ag by T cell-based immunotherapeutical strategies such as cancer vaccines and adoptive T cell transfer. The prerequisite for a successful T cell-based therapy is the induction of T cells capable of recognizing the HER2-expressing tumor cells. In this study, we generated human cytotoxic T cell clones directed against the HER2(369-377) epitope known to be naturally presented with HLA-A*0201. Those HER2-reactive CTLs, which were also tumor lytic, exhibited a similar lysis pattern dividing the targets in lysable and nonlysable tumor cells. Several HER2-expressing tumor cells became susceptible to CTL-mediated lysis after IFN-gamma treatment and, in parallel, up-regulated molecules of the Ag-presenting machinery, indicating that the tumor itself also contributes to the success of CTL-mediated killing. Some of the HER2(369-377)-reactive T cells specifically cross-reacted with the corresponding peptides derived from the family members HER3 and/or HER4 due to a high sequence homology. The epitopes HER3(356-364) and HER4(361-369) were endogenously processed and contributed to the susceptibility of cell lysis by HER cross-reacting CTLs. The principle of "double" or "triple targeting" the HER Ags by cross-reacting T cells will impact the further development of T cell-based therapies.
Department of Hematology/Oncology, Technical University of Munich, Klinikum Rechts der Isar, Munich, Germany.
Heinke
H
Conrad
Kerstin
K
Gebhard
Holger
H
Krönig
Julia
J
Neudorfer
Dirk H
DH
Busch
Christian
C
Peschel
Helga
H
Bernhard
D017951:Antigen Presentation / Q000276:immunology; D045744:Cell Line, Tumor; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology / Q000378:metabolism; D020014:K562 Cells; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D020893:Receptor, ErbB-3 / Q000276:immunology / Q000378:metabolism*; D066247:Receptor, ErbB-4; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism*
D018984:Epitopes, T-Lymphocyte; D066246:ErbB Receptors; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C474513:HER-2 peptide E75 (369-377), human; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human