Frameshift-mutation-derived peptides as tumor-specific antigens in inherited and spontaneous colorectal cancer

The functional role and specificity of tumor infiltrating lymphocytes (TIL) is generally not well characterized. Prominent lymphocyte infiltration is the hallmark of the most common form of hereditary colon cancer, hereditary nonpolyposis colon cancer (HNPCC) and the corresponding spontaneous colon cancers with the microsatellite instability (MSI) phenotype. These cancers are caused by inherited or acquired defects in the DNA mismatch-repair mach inery. The molecular mechanism behind the MSI phenotype provides a clue to understanding the lymphocyte reaction by allowing reliable prediction of po tential T cell epitopes created by frameshift mutations in candidate genes carrying nucleotide repeat sequences, such as TGF beta RII and BAX These tu mors therefore represent an interesting human system for studying TIL and c haracterizing tumor-specific T cells. We here describe T cell reactivity ag ainst several T helper cell epitopes, representing a common frameshift muta tion in TGF beta RII, in TIL and peripheral blood lymphocytes from patients with MSI+ tumors. The peptide SLVRLSSCVPVALMSAMTTSSSQ was recognized by T cells from two of three patients with spontaneous MSI+ colon cancers and fr om all three patients with HNPCC. Because such mutations are present in 90% of cancers within this patient group, these newly characterized epitopes p rovide attractive targets for cancer vaccines, including a prophylactic vac cine for individuals carrying a genetic disposition for developing HNPCC.