Abstract
Therapeutic antibodies that target immune checkpoints have revolutionized cancer therapy. While these checkpoints restrain T cell activation in response to antigen engagement, checkpoint inhibitors de-repress such tumor-associated T cells, and have generated major clinical responses in multiple tumor types. Nonetheless, the vast majority of cancers remain resistant to this therapeutic approach as currently deployed, either through intrinsic or acquired resistance mechanisms. One key question involves the identity of the tumor targets which effector T cells recognize. Tumor-specific mutant epitopes (often called neoantigens) represent a favored example, whose recognition has been demonstrated in certain contexts. While potentially helpful in identifying likely therapeutic opportunities (such as cancers harboring DNA repair defects), numerous cancers are relatively deficient in neoantigen loads. This commentary discusses the prospect that a phenomenon of "epitope spreading" may occur in certain high mutation contexts, giving rise to T cell responses against non-mutated/wild-type lineage proteins. Recent evidence is also discussed that suggests this mechanism may be exploited to purposely trigger epitope spreading and induce systemic tumor eradication in neoantigen-deficient cancers.