Enhancement of dendritic cell-based vaccine potency by targeting antigen to endosomal/lysosomal compartments.
Dendritic cells (DCs) are the central players in cancer immunotherapy because of their distinct ability to prime immune responses. In previous work with DNA vaccines, we described an intracellular targeting approach that routed a nuclear/cytoplasmic antigen, human papillomavirus (HPV) type 16 E7, into the endosomal and lysosomal compartments. It does so by linking E7 with the sorting signal of lysosome-associated membrane protein 1 (Sig/LAMP-1) to enhance the presentation of E7 antigen to MHC class I-restricted CD8(+) T cells, as well as to MHC class II-restricted CD4(+) T cells. To date, the Sig/LAMP-1 targeting strategy has not been tested in the context of DC-based vaccines. This study was designed to determine whether targeting HPV-16 E7 to the endosomal/lysosomal compartment can enhance the potency of DC vaccines. In immunological studies, DC-Sig/E7/LAMP-1 dramatically increased in vitro activation and in vivo expansion of E7-specific CD4(+) and CD8(+) T cells, compared with DC-E7 and DC-No insert. More importantly, in both tumor prevention and tumor treatment assays, DC-Sig/E7/LAMP-1 generated greater anti-tumor immunity against TC-1 than DC-E7. Our results demonstrate that linkage of the antigen gene to an endosomal/lysosomal targeting signal may greatly enhance the potency of DC-based vaccines.
Kang
Tae Heung
TH
Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, 516 Gojan-1 Dong, Ansan-Si, Gyeonggi-Do 425-707, South Korea.
Lee
Jin Hyup
JH
Bae
Hyun Cheol
HC
Noh
Kyung Hee
KH
Kim
Jin Hee
JH
Song
Chung Kil
CK
Shin
Byung Chul
BC
Hung
Chien-Fu
CF
Wu
T-C
TC
Park
Jong-Sup
JS
Kim
Tae Woo
TW
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D011992:Endosomes / Q000235:genetics / Q000276:immunology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051907:Lysosomal Membrane Proteins / Q000235:genetics / Q000276:immunology; D008247:Lysosomes / Q000235:genetics / Q000276:immunology*; D051379:Mice; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D021382:Protein Sorting Signals / Q000235:genetics; D052118:Lysosomal-Associated Membrane Protein 1
D019496:Cancer Vaccines; D000949:Histocompatibility Antigens Class II; D051907:Lysosomal Membrane Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D021382:Protein Sorting Signals; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C059731:oncogene protein E7, Human papillomavirus type 16