We have recently discovered that renal cell carcinomas (RCC) over-express the receptor tyrosine kinase (RTK) EphA2 relative to normal kidney tissue, and that this is associated with an enhanced metastatic phenotype and an adverse clinical prognosis. Cross-linking of tumor cell-expressed EphA2 molecules using either ligand Ephrin A1-lg fusion proteins or activating anti-EphA2 antibodies results in RTK phosphorylation, followed by receptor internalization, c-Cbl-dependent ubiquitination and proteasome-dependent degradation. As a consequence, treated tumor cells acquire a more benign phenotype and concomitantly, our preliminary data suggest they conditionally upregulate their expression of EphA2-derived epitopes presented in MHC class I complexes. Using EphA2-specific CTL lines and clones, we have shown in preliminary data that this results in improved recognition and killing of RCC tumor cells by anti-EphA2 CD8+ T cells in vitro. We have also recently observed that pharmacologic inhibition of protein tyrosine phosphatases (PTP) also serves to increase EphA2 phosphorylation and proteasomal processing, theoretically making EphA2 peptides accessible to the MHC class I biosynthetic pathway. We hypothesize that EphA2 ligand agonists and PTP inhibitors may act synergistically in promoting enhanced tumor cell recognition by CTLs. Furthermore, we hypothesize that combinational immunotherapies consisting of the adoptive transfer of EphA2-specific T cells or EphA2-based vaccines designed to elicit specific CTLs and conditional activation of EphA2 degradation and proteasomal processing via locoregional administration of EphA2 ligand agonists or PTP inhibitors will promote an improvement in RCC regression rates and foster objective clinical responses. Lastly, since numerous other RTKs may be over-expressed by (at least certain subsets of) RCC including; EGF-R, Her2/neu, among others, we propose to assess the generality of conditionally promoting the proteasomal processing of these RTKs using this strategy, with the intent to force tumor cells to simultaneously overexpress a broad repertoire of RTK-derived epitopes in MHC class I complexes to effector CTLs. Under such conditions, concerns related to specific antigen-loss tumor progression would be reduced and the likelihood of immune recognition and therapeutic killing of treated tumor cells would be hypothetically improved. ? ?
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