Frameshift peptide-derived T-cell epitopes: a source of novel tumor-specific antigens

Microsatellite instability (MSI) caused by defective DNA mismatch repair (M MR) is a hallmark of hereditary nonpolyposis colorectal cancers (HNPCC) but also occurs in about 15% of sporadic tumors. If instability affects micros atellites in coding regions, translational frameshifts lead to truncated pr oteins often marked by unique frameshift peptide sequences at their C-termi nus. Since MSI tumors show enhanced lymphocytic infiltration and our previo us analysis identified numerous coding mono- and dinucleotide repeat-bearin g candidate genes as targets of genetic instability, we examined the role o f frameshift peptides in triggering cellular immune responses. Using peptid e pulsed autologous CD40-activated B cells, we have generated cytotoxic T l ymphocytes (CTL) that specifically recognize HLA-A2.I-restricted peptides d erived from frameshift sequences. Among 16 frameshift peptides predicted fr om mutations in 8 different genes, 3 peptides conferred specific lysis of t arget cells exogenously loaded with cognate peptide, One peptide derived fr om a (-I) frameshift mutation in the TGF beta IIR gene gave rise to a CTL b ulk culture capable of lysing the MSI colorectal cancer cell line HCTII6 ca rrying this frameshift mutation. Given the huge number of human coding micr osatellites and assuming only a fraction being mutated and encoding immunol ogically relevant peptides in MSI tumors, frameshift protein sequences repr esent a novel subclass of tumor-specific antigens, It is tempting to specul ate that a frameshift peptide-directed vaccination approach not only could offer new treatment modalities for existing MSI tumors but also might benef it asymptomatic at-risk individuals in HNPCC families by a prophylactic vac cination strategy. (C) 2001 Wiley-Liss, Inc.