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Heat Shock Protein 90 Inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin Enhances EphA2⁺ Tumor Cell Recognition by Specific CD8⁺ T Cells

Departments of ¹ Immunology and ² Dermatology, University of Pittsburgh School of Medicine; ³ University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania and ⁴ Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Walter J. Storkus, University of Pittsburgh School of Medicine, W1041.2 Biomedical Sciences Tower, 200 Lothrop Street, Pittsburgh, PA 15213. Phone: 412-648-9981; Fax: 412-383-5857; E-mail: storkuswj{at}upmc.edu.

Key Words: EphA2 • HSP90 inhibitor • 17-DMAG • CD8⁺ T cells • proteasome

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]