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Combining the Antigen Processing Components TAP and Tapasin Elicits Enhanced Tumor-Free Survival

Authors' Affiliations: ¹ Michael Smith Laboratories, ² Biomedical Research Center, ³ Departments of Zoology, ⁴ Microbiology and Immunology, and ⁵ Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada

Requests for reprints: Wilfred A. Jefferies, Biomedical Research Center, University of British Columbia, 2222 Health Sciences Mall, Vancouver, B.C. V6T 1Z3 Canada. Phone: 1-604-822-6961; Fax: 1-604-822-7815; E-mail: wilf{at}brc.ubc.ca.

Purpose: Tpn is a member of the MHC class I loading complex and functions to bridge the TAP peptide transporter to MHC class I molecules. Metastatic human carcinomas often express low levels of the antigen-processing components Tapasin and TAP and display few functional surface MHC class I molecules. As a result, carcinomas are unrecognizable by effector CTLs. The aim of this study is to examine if Tapasin (Tpn) plays a critical role in the escape of tumors from immunologic recognition.

Experimental Design: To test our hypothesis, a nonreplicating adenovirus vector encoding human Tpn (AdhTpn) was constructed to restore Tpn expression in vitro and in vivo in a murine lung carcinoma cell line (CMT.64) that is characterized by down-regulation of surface MHC class I due to deficiency in antigen-processing components.

Results: Ex vivo, Tpn expression increased surface MHC class I and restored susceptibility of tumor cells to antigen-specific CTL killing, and AdhTpn infection of dendritic cells also significantly increased cross-presentation and cross-priming. Furthermore, tumor-bearing animals inoculated with AdhTpn demonstrated a significant increase in CD8⁺ and CD4⁺ T cells and CD11c⁺ dendritic cells infiltrating the tumors. Provocatively, whereas syngeneic mice bearing tumors that were inoculated with AdhTpn a significant reduction in tumor growth and increased survival compared with vector controls, combining AdhTpn inoculation with AdhTAP1 resulted in a significant augmentation of protection from tumor-induced death than either component alone.

Conclusions: This is the first demonstration that Tpn alone can enhance survival and immunity against tumors but additionally suggests that Tpn and TAP should be used together as components of immunotherapeutic vaccine protocols to eradicate tumors.