| Summary: | The <i>RAS</i> mutations are the most frequently occurring somatic mutations in humans, and several studies have established that T cells from patients with <i>RAS</i>-mutant cancer recognize and kill <i>RAS</i>-mutant cells. Enhancing the T cell response via therapeutic cancer vaccination against mutant <i>RAS </i>results in a clinical benefit to patients; thus, T cells specific to <i>RAS</i> mutations are effective at battling cancer. As the theory of cancer immuno-editing indicates that healthy donors may clear malignantly transformed cells via immune-mediated killing, and since T cells have been shown to recognize <i>RAS</i>-mutant cancer cells, we investigated whether healthy donors harbor T-cell responses specific to mutant RAS. We identified strong and frequent responses against several epitopes derived from the RAS codon 12 and codon 13 mutations. Some healthy donors demonstrated a response to several mutant epitopes, and some, but not all, exhibited cross-reactivity to the wild-type RAS epitope. In addition, several T cell responses were identified against mutant <i>RAS</i> epitopes in healthy donors directly ex vivo. Clones against mutant RAS epitopes were established from healthy donors, and several of these clones did not cross-react with the wild-type epitope. Finally, CD45RO<sup>+</sup> memory T cells from healthy donors demonstrated a strong response to several mutant RAS epitopes. Taken together, these data suggest that the immune system in healthy donors spontaneously clears malignantly transformed <i>RAS</i>-mutant cells, and the immune system consequently generates T-cell memory against the mutations.
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