Abstract Deficiencies in MHC Class I antigen presentation by tumor cells is a significant barrier to effective cancer immunotherapy. Therefore, combinational therapies that enhance tumor-associated antigen (TAA) presentation in tumor MHC Class I molecules while coordinately stimulating TAA-specific immunity would be expected to yield a greater clinical benefit. We have previously showed that in vitro treatment of tumor cells with 17-DMAG results in transient (proteasome-dependent) degradation of the EphA2, a TAA that is over expressed in several cancers, accompanied by increased presentation of EphA2 peptides on MHC class I complexes on tumor cells. To further characterize the therapeutic potential of this approach, we assessed the efficacy of a rationally-designed combinational therapy incorporating 17-DMAG and EphA2-targeted immunotherapy in murine tumor models. In vivo administration of 17-DMAG promoted: i) dramatically slowed tumor growth; ii) Enhanced recognition of tumor cells by anti-EphA2 CD8+ T cells; iii) Reduction in the frequency of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) in the tumor microenvironment, and iv) activation of tumor-associated vascular endothelial cells thereby facilitating Type-1 T cell infiltration. When combined with EphA2-specific active vaccination or the adoptive transfer of EphA2-specific CD8+ T cells, 17-DMAG co-treatment yielded a superior tumor therapeutic regimen that was capable of rendering animals free of disease.
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