| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
,||
Departments of
* Dermatology and
Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
Department of Molecular Therapeutics, Osaka University, Osaka, Japan;
Cleveland Clinic Foundation, Cleveland, OH 44195;
¶ MedImmune, Gaithersburg, MD 20878; and the
|| University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a National Institutes of Health (NIH) Immunology Training Grant 5T32 CA82084 (to C.J.H.), NIH R01 Grant CA 114071 (to W.J.S.), and a Developmental Research Pilot Project sponsored by the University of Pittsburgh’s Specialized Program of Research Excellence (SPORE) in Head & Neck Cancer P50 CA097190 (to A.K.W.).
2 A.K.W. and C.J.H. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Amy K. Wesa, Department of Dermatology, University of Pittsburgh School of Medicine, W1045 BST, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail address: wesaak{at}upmc.edu
4 Abbreviations used in this paper: RTK, receptor tyrosine kinase; EGFR, epidermal growth factor receptor; Hu-SCID, humanized SCID; MFI, mean fluorescence intensity.
This article has been cited by other articles:
|
|
 |
|
  M. Kawabe, M. Mandic, J. L. Taylor, C. A. Vasquez, A. K. Wesa, L. M. Neckers, and W. J. Storkus Heat Shock Protein 90 Inhibitor 17-Dimethylaminoethylamino-17-Demethoxygeldanamycin Enhances EphA2+ Tumor Cell Recognition by Specific CD8+ T Cells Cancer Res., September 1, 2009; 69(17): 6995 - 7003. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
