About 15% of all human colorectal, gastric, and endometrial
tumors, and the majority of
tumors in patients suffering from
hereditary nonpolyposis colorectal cancer syndrome, are caused by loss of DNA mismatch repair functions. In the affected
cancer cells, this results in insertion or deletion mutations at short, repetitive DNA sequences referred to as microsatellites. Such mutations in coding microsatellites (cMS) cause translational frameshifts that may destroy gene function. These frameshift mutations could also cause the translation of immunogenic neopeptides at the carboxy terminus. Several such mutations have been identified recently. However, since none of the frameshift-induced neopeptides identified so far is generated in all
cancer cells with
microsatellite instability (MSI), we aim to define a broad but comprehensive set of frameshift
peptides (FSPs) that might be combined in a
multivalent vaccine for MSI+
cancers. Here, we characterize the immunogenic properties of five additional HLA-A0201-restricted frameshift-induced neopeptides derived from mutations in three cMS-containing genes (
Caspase-5, TAF-1b, and HT001) that are frequently hit in MSI+
cancer cells. One Caspase-5-derived FSP, (67)-FLIIWQNTM (FSP26), was identified as a novel HLA-A0201-restricted CTL
epitope. FSP26-specific CTLs efficiently lysed colon
carcinoma cells expressing
HLA-A0201 and the underlying (-1) mutation. This mutation in an
A(10) cMS is observed in up to 66% of MSI+
colorectal cancers. Thus, this newly identified CTL
epitope may be another essential component of a
multivalent vaccine against
cancers with MSI.