Cell
Volume 183, Issue 6, 10 December 2020, Pages 1634-1649.e17
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Article
Shared Immunogenic Poly-Epitope Frameshift Mutations in Microsatellite Unstable Tumors

https://doi.org/10.1016/j.cell.2020.11.004Get rights and content
open access

Highlights

  • MSI-H tumors are enriched in recurrent shared immunogenic frameshifts

  • Shared frameshifts are expressed on RNA and protein levels

  • Shared frameshifts produce exceptional T cell responses

Summary

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.

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