CTLs directed against HER2 specifically cross-react with HER3 and HER4

J Immunol. 2008 Jun 15;180(12):8135-45. doi: 10.4049/jimmunol.180.12.8135.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation / immunology
  • Cell Line, Tumor
  • Clone Cells
  • Cytotoxicity Tests, Immunologic*
  • Epitopes, T-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / metabolism
  • ErbB Receptors / immunology
  • ErbB Receptors / metabolism*
  • HLA-A2 Antigen / immunology
  • HLA-A2 Antigen / metabolism
  • Humans
  • Immunodominant Epitopes / immunology
  • Immunodominant Epitopes / metabolism
  • K562 Cells
  • Peptide Fragments / immunology*
  • Peptide Fragments / metabolism*
  • Protein Binding / immunology
  • Receptor, ErbB-2 / immunology*
  • Receptor, ErbB-3 / immunology
  • Receptor, ErbB-3 / metabolism*
  • Receptor, ErbB-4
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism*


  • Epitopes, T-Lymphocyte
  • HER-2 peptide E75 (369-377), human
  • HLA-A2 Antigen
  • Immunodominant Epitopes
  • Peptide Fragments
  • ERBB2 protein, human
  • ERBB4 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2
  • Receptor, ErbB-3
  • Receptor, ErbB-4