Identification of tumor antigen-specific cytotoxic T lymphocytes cross-recognizing allogeneic major histocompatibility class I molecules

Adoptive immunotherapy of cancer utilizes tumor antigen-specific cytotoxic T lymphocytes (CTL) as mediators of a targeted anti-tumor effect. In this study, we show that such CTL can be able to cross-recognize allogeneic major histocompatibility complex (MHC) molecules in a phenomenon of molecular mimicry. A self histo-leukocyte antigen (HLA) A*0201-restricted CTL specific for peptide MT27-35 from the human differentiation antigen Melan-A/MART-1 was shown to cross-recognize allogeneic A*0220 molecules which differ from syngeneic A*0201 for a single amino acid substitution at position 66 of the antigen-binding groove. A*0220 molecules were recognized on a variety of human cells of different histological origin but not on COS-7 cells. A second self-A*0201-restricted CTL, specific for peptide D10/6-271 encoded by the tumor-specific DAM-gene family, was shown to cross-recognize allogeneic B*3701 molecules which differ from syngeneic A*0201 by 32 amino acids in the peptide antigen-binding cleft. B*3701 molecules were recognized on a variety of cell types including COS-7 cells. These data raise new safety issues for clinical trials of cancer immunotherapy using adoptive transfer of in vitro generated, allogeneic CTL with specific anti-tumor activity.