Combining the antigen processing components TAP and Tapasin elicits enhanced tumor-free survival.
OBJECTIVE
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.


METHODS
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.
Lou
Yuanmei
Y
Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada.
Basha
Genc
G
Seipp
Robyn P
RP
Cai
Bing
B
Chen
Susan S
SS
Moise
Alexander R
AR
Jeffries
Andrew P
AP
Gopaul
Ray S
RS
Vitalis
Timothy Z
TZ
Jefferies
Wilfred A
WA
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000276:immunology*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology; D018572:Disease-Free Survival; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating; D026901:Membrane Transport Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015996:Survival Rate; D013602:T-Lymphocytes, Cytotoxic
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D026901:Membrane Transport Proteins; C073119:TAP1 protein, human; C107762:tapasin