title: Enhancement in specific CD8+ T cell recognition of EphA2+ tumors in vitro and in vivo after treatment with ligand agonists.
abstract: 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.
authors.affiliation: Department of Dermatology, University of Pittsburgh School ofMedicine, Pittsburgh, PA 15213, USA. wesaak@upmc.edu
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wesa
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Herrem
authors.forename: Maja
authors.initials: M
authors.lastname: Mandic
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor
authors.forename: Cecilia
authors.initials: C
authors.lastname: Vasquez
authors.forename: Mayumi
authors.initials: M
authors.lastname: Kawabe
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tatsumi
authors.forename: Michael S
authors.initials: MS
authors.lastname: Leibowitz
authors.forename: James H
authors.initials: JH
authors.lastname: Finke
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Bukowski
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bruckheimer
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kinch
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000912:Antibodies, Neoplasm / Q000494:pharmacology; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000276:immunology*; D009368:Neoplasm Transplantation; D010455:Peptides / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D017434:Protein Structure, Tertiary; D036104:Receptor, EphA2 / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D018984:Epitopes, T-Lymphocyte; D009363:Neoplasm Proteins; D010455:Peptides; D036104:Receptor, EphA2; D046988:Proteasome Endopeptidase Complex