The immune system can be efficiently stimulated and targeted to specific
antigens 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-associated
antigens recognized by cellular immunity; (b)
antigens expressed on the majority 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 naturally 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
ovarian cancer, is also recognized in
breast cancer. Both immunodominant
E39 (FBP, 191-199) and subdominant E41 (FBP, 245-253)
epitopes are presented by
HLA-A2 in these
cancers. These
peptides are efficient at amplifying the response 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 enhanced cytotoxicity not only against
peptide-loaded targets but also against FBP-expressing epithelial
tumors of different histologies. Furthermore, FBP
peptides induced E39-specific CTLs and E39- and E41-specific IFN-gamma and 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 breast, lung, colorectal, and
renal cell carcinomas, along with pronounced differential overexpression in malignant tissues compared with the extremely limited expression in normal epithelium, suggests the exciting potential of a widely applicable FBP-based
vaccine in epithelial
cancers.