Vaccination with an adenoviral vector encoding the tumor antigen directly linked to invariant chain induces potent CD4(+) T-cell-independent CD8(+) T-cell-mediated tumor control.
Antigen-specific immunotherapy is an attractive strategy for cancer control. In the context of antiviral vaccines, adenoviral vectors have emerged as a favorable means for immunization. Therefore, we chose a strategy combining use of these vectors with another successful approach, namely linkage of the vaccine antigen to invariant chain (Ii). To evaluate this strategy we used a mouse model, in which an immunodominant epitope (GP33) of the LCMV glycoprotein (GP) represents the tumor-associated neoantigen. Prophylactic vaccination of C57BL/6 mice with a replication-deficient human adenovirus 5 vector encoding GP linked to Ii (Ad-Ii-GP) resulted in complete protection against GP33-expressing B16.F10 tumors. Therapeutic vaccination with Ad-Ii-GP delayed tumor growth by more than 2 wk compared with sham vaccination. Notably, therapeutic vaccination with the linked vaccine was significantly better than vaccination with adenovirus expressing GP alone (Ad-GP), or GP and Ii unlinked (Ad-GP+Ii). Ad-Ii-GP- induced tumor control depended on an improved generation of the tumor-associated neoantigen-specific CD8(+) T-cell response and was independent of CD4(+) T cells. IFN-gamma was shown to be a key player during the tumor degradation. Finally, Ad-Ii-GP but not Ad-GP vaccination can break the immunological non-reactivity in GP transgenic mice indicating that our vaccine strategy will prove efficient also against endogenous tumor antigens.
Sorensen
Maria R
MR
University of Copenhagen, Institute of International Health, Immunology and Microbiology, Copenhagen, Denmark.
Holst
Peter J
PJ
Pircher
Hanspeter
H
Christensen
Jan P
JP
Thomsen
Allan R
AR
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005802:Genes, MHC Class II / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D019496:Cancer Vaccines; D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C479900:glycoprotein C, lymphocytic choriomeningitis virus; C094244:glycoprotein peptide 33-41, Lymphocytic choriomeningitis virus; C045084:invariant chain; D007371:Interferon-gamma