By analyzing tumor whole exome sequencing data in TCGA and querying the Cancer Cell Line Encyclopedia, Roudko and Bozkus et al. showed that microsatellite instability-high (MSI-H) endometrial, colorectal, and stomach cancers had high recurring frameshift mutation loads that frequently encoded polyepitope neopeptides that bound to MHC alleles prevalent in patients with MSI-H cancers, more so in anti-PD-1 responders. Analysis of The Immune Epitope Database showed these tumor neoantigens were distinct from self and viral antigens. Derived, predicted neopeptides stimulated blood CD8+ T cells from healthy donors and patients to make IFNγ and TNFα.
Contributed by Paula Hochman
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.