| Abstract: |
Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutation burden and responsiveness to checkpoint blockade. We identified tumor-specific frameshifts encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal, and stomach cancers. Epitopes derived from these shared frameshifts have high population occurrence rates, wide presence in many tumor subclones, and are predicted to bind to the most frequent MHC alleles in MSI-H patient cohorts. Neoantigens arising from these mutations are distinctly unlike self and viral antigens, signifying novel groups of potentially highly immunogenic tumor antigens. We further confirmed the immunogenicity of frameshift peptides in T cell stimulation experiments using blood mononuclear cells isolated from both healthy donors and MSI-H cancer patients. Our study uncovers the widespread occurrence and strong immunogenicity of tumor-specific antigens derived from shared frameshift mutations in MSI-H cancer and Lynch syndrome patients, suitable for the design of common “off-the-shelf” cancer vaccines. © 2020 Elsevier Inc. Tumors that have high levels of mutations within microsatellites (MSI-H) demonstrate specific frameshifts that are then expressed at the RNA and protein levels across endometrial, colorectal, and stomach cancers. Epitopes from these frameshifts yield neoantigens that are distinct from self and viral antigens and elicit T cell responses. © 2020 Elsevier Inc. |
