Emex 3 v 3 . 11 . 1649
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Patients plotted in columns genes plotted in rows. Unsupervised hierarchical clustering of shared fs-mutation load (Left) and corresponding expression FPKM values of frameshifted genes (Right) in MSI-H UCEC (Top), COAD (Center) and STAD (Bottom) tumors. Tumor allele frequency of nine shared frameshift mutations in normal (Top) and tumor (Bottom) tissues of MSI-H UCEC TCGA patients. Each bar represents the difference score per each MHC allele. Friedman difference test, measuring the difference between pMHC interactions found in all MSI-H UCEC patients (ALL) and either pMHC interactions in each fs-peptide separately or combined together (POOL). Genomic and expression properties of shared fs-mutations in MSI-H tumors. Quantification of MHC-I epitopes derived from 9 shared fs-peptides of MSI-H UCEC cohort shown per each patient (rows, left panel) or each MHC-I allele (rows, right panel). MHC-I epitope mapping of 46 shared fs-peptides from MSI-H UCEC, COAD and STAD tumors combined together. Color of the dot reflects the somatic score of the fs-mutation. Size of the circle represents the number of predicted pMHC interactions. Number of predicted 9-mer epitopes per peptide (X-axis) is plotted against the number of predicted interacting MHC alleles (Y-axis). Each dot represents a fs-peptide shared in at least 20% of patients in each cohort. Three scatterplots showing the selection criteria for identification of shared fs-peptides in MSI-H UCEC, COAD and STAD. Scatterplots of patient frequencies of frameshifted genes (LEFT), fs-peptides (CENTER) and fs-epitopes (RIGHT) in UCEC, STAD and COAD MSI-H tumors. All rights reserved.įrequencies of shared fs-events and fs-peptides, and fs-epitope distribution in STAD, COAD and UCEC MSI-H tumors.
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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.Ĭopyright © 2020 Elsevier Inc. 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. Neoantigens arising from these mutations are distinctly unlike self and viral antigens, signifying novel groups of potentially highly immunogenic tumor antigens. 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. We identified tumor-specific frameshifts encoding multiple epitopes that originated from indel mutations shared among patients with MSI-H endometrial, colorectal, and stomach cancers. Microsatellite instability-high (MSI-H) tumors are characterized by high tumor mutation burden and responsiveness to checkpoint blockade.