The
EphA2 receptor tyrosine kinase is an attractive therapeutic target that is commonly overexpressed on solid
tumors, with the degree of overexpression associated with
disease progression, metastatic potential, and poor prognosis. Agonistic mAbs or
ligand (ephrinA1)-Fc fusion
protein are capable of inducing EphA2 internalization and degradation, thereby (at least transiently) eliminating the influence of this
oncoprotein. We and others have also shown that EphA2 contains multiple
peptide epitopes that can be recognized by effector CD4(+) and CD8(+) T cells isolated from
tumor-bearing patients. Herein, we show that "agonist"
reagents that trigger the
proteasome-dependent degradation of
tumor cell EphA2 result in the improved presentation of
peptides derived from (both the extracellular and intracellular domains of) EphA2 in MHC class I complexes expressed on the
tumor cell membrane for at least 48 h, as manifested by increased recognition by EphA2-specific CD8(+) T cells in vitro. We also observed that while delivery of ephrinA1-Fc fusion
protein or agonist mAb into EphA2(+)
tumor lesions promotes EphA2 degradation in situ, this single administration of agent does not dramatically alter
tumor progression in a humanized SCID model. However, when combined with the adoptive transfer of normally nontherapeutic (human) anti-EphA2 CD8(+) CTL, this dual-agent regimen results in complete
tumor eradication. These results suggest that strategies targeting the conditional
proteasome-mediated destruction of
tumor cell EphA2 may enable EphA2-specific CD8(+) T cells (of modest functional avidity) to realize improved therapeutic potential.