Vaccine implications of folate binding protein, a novel cytotoxic T lymphocyte-recognized antigen system in epithelial cancers

The immune system can be efficiently stimulated and targeted to specific an tigens expressed exclusively or preferentially by experimental cancers. The foremost limitations to extending this vaccine technology to the prevalent epithelial-derived cancers are the lack of: (a) identified tumor-associate d antigens recognized by cellular immunity; (b) antigens expressed on the m ajority of tumor cells during disease progression; and (c) immunogenic CTL epitopes, To date, only HER-2/neu has been shown to be the source of natura lly occurring, MHC-restricted, CTL-recognized peptides in epithelial tumors . In this study, we demonstrate that the human high-affinity folate binding protein (FBP), which is a source of antigenic peptides recognized in ovari an cancer, is also recognized in breast cancer. Both immunodominant E39 (FB P, 191-199) and subdominant E41 (FBP, 245-253) epitopes are presented by HL A-A2 in these cancers. These peptides are efficient at amplifying the respo nse of tumor-associated lymphocyte populations in terms of lytic function, enhanced proliferation, and specific IFN-gamma release. On a per cell basis , tumor-associated lymphocytes stimulated with the FBP peptides exhibit enh anced cytotoxicity not only against peptide-loaded targets but also against FBP-expressing epithelial tumors of different histologies, Furthermore, FB P peptides induced E39-specific CTLs and E39- and E41-specific IFN-gamma an d IP-10 secretion in certain healthy donors. The broad distribution of FBP among >90% of ovarian and endometrial carcinomas, as well as 20-50% of brea st, lung, colorectal, and renal cell carcinomas, along,vith pronounced diff erential overexpression in malignant tissues compared with the extremely li mited expression in normal epithelium, suggests the exciting potential of a widely applicable FBP-based vaccine in epithelial cancers.