Shared Immunogenic Poly-Epitope Frameshift Mutations in Microsatellite Unstable Tumors
Menée notamment à l'aide de cellules mononucléées extraites d'échantillons sanguins issus de donneurs sains et de patients atteints d'un cancer avec haute instabilité des microsatellites, cette étude identifie des néo-antigènes comportant des épitopes hautement immunogènes résultant de mutations avec décalage du cadre de lecture communes à plusieurs types tumoraux (endomètre, côlon-rectum et estomac)
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.
Cell , résumé, 2019