Induction of protective CTL immunity against peptide transporter TAP-deficient tumors through dendritic cell vaccination.
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.
Chambers
Benedict
B
Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. Benedict.Chambers@ki.se
Grufman
Per
P
Fredriksson
Vanoohi
V
Andersson
Kenth
K
Roseboom
Marjet
M
Laban
Sandra
S
Camps
Marcel
M
Wolpert
Elisabeth Z
EZ
Wiertz
Emmanuel J H J
EJ
Offringa
Rienk
R
Ljunggren
Hans-Gustaf
HG
van Hall
Thorbald
T
D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005354:Fibrosarcoma / Q000276:immunology / Q000517:prevention & control; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology; D008223:Lymphoma / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000517:prevention & control; D009842:Oligopeptides / Q000037:antagonists & inhibitors / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D009842:Oligopeptides; C080396:trypsinogen activation peptide