Data from Heat Shock Protein 90 Inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin Enhances EphA2<sup>+</sup> Tumor Cell Recognition by Specific CD8<sup>+</sup> T Cells

EphA2, a member of the receptor tyrosine kinase family, is commonly expressed by a broad range of cancer types, where its level of (over)expression correlates with poor clinical outcome. Because tumor cell expressed EphA2 is a nonmutated “self” protein, specific CD8⁺ T cells are subject to self-tolerance mechanisms and typically exhibit only moderate-to-low functional avidity, rendering them marginally competent to recognize EphA2⁺ tumor cells in vitro or in vivo. We have recently reported that the ability of specific CD8⁺ T cells to recognize EphA2⁺ tumor cells can be augmented after the cancer cells are pretreated with EphA2 agonists that promote proteasomal degradation and up-regulated expression of EphA2/class I complexes on the tumor cell membrane. In the current study, we show that treatment of EphA2⁺ tumor cells with the irreversible heat shock protein 90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), similarly enhances their recognition by EphA2-specific CD8⁺ T-cell lines and clones in vitro via a mechanism that is dependent on proteasome and transporter-associated protein function as well as the retrotranslocation of EphA2 into the tumor cytoplasm. When 17-DMAG and agonist anti-EphA2 monoclonal antibodies are coapplied, T-cell recognition of tumor cells is further increased over that observed for either agent alone. These studies suggest that EphA2 represents a novel heat shock protein 90 client protein and that the treatment of cancer patients with 17-DMAG–based “pulse” therapy may improve the antitumor efficacy of CD8⁺ T effector cells reactive against EphA2-derived epitopes. [Cancer Res 2009;69(17):6995–7003]