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Induction of Protective CTL Immunity against Peptide Transporter TAP-Deficient Tumors through Dendritic Cell Vaccination

¹ Center for Infectious Medicine and ² Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet; ³ Accuro Immunology, Stockholm, Sweden; and Departments of ⁴ Immunohematology and Blood Transfusion, ⁵ Medical Microbiology, and ⁶ Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands

Requests for reprints: Benedict Chambers, Center for Infectious Medicine, F59, Department of Medicine, Karolinska University Hospital, Huddinge, Karolinska Institutet, 141 86 Stockholm, Sweden. E-mail: Benedict.Chambers{at}ki.se.

A large proportion of human cancers show deficiencies in the MHC class I antigen-processing machinery. Such defects render tumors resistant to immune eradication by tumoricidal CTLs. We recently identified a unique population of CTL that selectively targets tumor immune-escape variants through recognition of MHC-presented peptides, termed TEIPP (T cell epitopes associated with impaired peptide processing), expressed on cells lacking functional TAP-peptide transporters. Previously, we showed that vaccination with TEIPP peptides mediates protection against TAP-deficient tumors. Here, we further explored the concept of TEIPP-targeted therapy using a dendritic cell (DC)–based cellular vaccine. Impairment of TAP function in DC induced the presentation of endogenous TEIPP antigens by MHC class I molecules, and immunization with these DCs protected mice against the outgrowth of TAP-deficient lymphomas and fibrosarcomas. Immune analysis of vaccinated mice revealed strong TEIPP-specific CTL responses, and a crucial role for CD8⁺ cells in tumor resistance. Finally, we show that TEIPP antigens could be successfully induced in wild-type DC by introducing the viral TAP inhibitor UL49.5. Our results imply that immune intervention strategies with TAP-inhibited DC could be developed for the treatment of antigen processing–deficient cancers in humans. [Cancer Res 2007;67(18):8450–5]