Conditional triggering of EphA2 epitope presentation results in the enhanced tumor cell recognition by specific CTL. (48.25)

The receptor tyrosine kinase EphA2 is over-expressed in numerous carcinomas in association with poor clinical prognosis. While pharmacologic agents that antagonize EphA2-mediated signaling could be contemplated as a therapy, a more preferred result would be to decrease tumor cell EphA2 expression while coordinately enhancing specific immune reactivity to tumor cells. We show that specific mAb triggers the internalization of EphA2, resulting in increased processing of EphA2 protein and presentation of EphA2-derived epitopes in tumor cell HLA class I complexes to CD8+ T cells (detected by IFN-γ production and CD107b translocation). Ab-enhanced CTL recognition is blocked by tumor cell co-treatment with Pseudomonas Exotoxin-A and proteasome inhibitors, but not by chloroquine, suggesting that internalized EphA2 complexes are rapidly translocated into the cytoplasm for delivery of peptides into the class I biosynthetic route. When combined with vaccines designed to augment the frequency of circulating anti-EphA2 CD8+ T cells, this agonist strategy may define an effective therapy for patients harboring EphA2+ cancers.