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Published on: April 20, 2021
An MSI tumor specific frameshift mutation in a coding microsatellite of MSH3 encodes for HLA-A0201-restricted CD8+
Yvette Garbe1, Claudia Maletzki, Michael Linnebacher
1National Center for Radiation Research in Oncology, Dresden, Germany.
Background:
Microsatellite instability (MSI) resulting from inactivation of the DNA mismatch repair system (MMR) characterizes a highly immunological subtype of colorectal carcinomas. Those tumors express multiple frameshift-mutated proteins which present a unique pool of tumor-specific antigens. The DNA MMR protein MSH3 is frequently mutated in MSI(+) colorectal tumors, thus making it an attractive candidate for T cell-based immunotherapies.
Methodology/Principal Findings:
FSP-specific CD8(+) T cells were generated from a healthy donor using reverse immunology. Those T cells specifically recognized T2 cells sensitized with the respective peptides. Specific recognition and killing of MSI(+) colorectal carcinoma cells harbouring the mutated reading frame was observed. The results obtained with T cell bulk cultures could be reproduced with T cell clones obtained from the same cultures. Blocking experiments (using antibodies and cold target inhibition) confirmed peptide as well as HLA-A0201-specificity.
Conclusions:
We identified two novel HLA-A0201-restricted cytotoxic T cell epitopes derived from a (-1) frameshift mutation of a coding A(8) tract within the MSH3 gene. These were (386)-FLLALWECSL (FSP18) and (387)-LLALWECSL (FSP19) as well as (403)-IVSRTLLLV (FSP23) and (402)-LIVSRTLLLV (FSP31), respectively. These results suggest that MSH3(-1) represents another promising MSI(+)-induced target antigen. By identifying two distinct epitopes within MSH3(-1), the sustained immunogenicity of the frameshift mutated sequence was confirmed. Our data therefore encourage further exploitation of MSH3 as a piece for peptide-based vaccines either for therapeutic or--even more important--preventive purposes.
Insights
Researchers identified novel T cell epitopes from the MSH3 gene in microsatellite instability (MSI) colorectal tumors. These findings support MSH3 as a target for cancer immunotherapy vaccines.
Area of Science:
- Immunology
- Oncology
- Genetics
Background:
- Microsatellite instability (MSI) in colorectal cancer is linked to DNA mismatch repair (MMR) system inactivation.
- MSI tumors express unique tumor-specific antigens from frameshift-mutated proteins.
- Mutations in the MSH3 MMR gene are common in MSI(+) colorectal tumors, making it a potential immunotherapy target.
Purpose of the Study:
- To identify and characterize T cell epitopes derived from mutated MSH3 in MSI(+) colorectal tumors.
- To evaluate the potential of these epitopes for T cell-based immunotherapies.
Main Methods:
- Generated MSH3 frameshift peptide (FSP)-specific CD8(+) T cells using reverse immunology.
- Assessed T cell recognition and killing of MSI(+) colorectal cancer cells.
- Confirmed epitope and HLA-A0201 restriction using blocking experiments.
Main Results:
- Identified two novel HLA-A0201-restricted cytotoxic T cell epitopes from a frameshift mutation in the MSH3 gene.
- Demonstrated specific recognition and killing of MSI(+) colorectal carcinoma cells by generated T cells.
- Confirmed sustained immunogenicity of MSH3 frameshift mutations.
Conclusions:
- MSH3 frameshift mutations represent promising targets for MSI(+)-induced immunotherapy.
- Identified MSH3 epitopes can be utilized for peptide-based vaccines for therapeutic or preventive cancer treatment.
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