Multistep process through which adenoviral vector vaccine overcomes anergy to tumor-associated antigens.
Our goal in the present work was to characterize the multiple steps involved in overcoming the anergy that exists in tumor hosts to tumor-associated antigen (TAA). Our studies showed that the subcutaneous injection of the Ad-sig-TAA/ecdCD40L vector resulted in secretion of the TAA/ecdCD40L protein for at least 10 days from infected cells. Binding of the TAA/ecdCD40L protein to dendritic cells (DCs) resulted in the induction of CCR-7 chemokine receptor expression and cytokine release. This was followed by migration of the DCs to regional lymph nodes. Tetramer staining, enzyme-linked immunospot (ELISPOT) assay, and cytotoxicity assay all showed that the Ad-sig-TAA/ecdCD40L vector increased the levels of splenic CD8(+) T cells specific for the 2 TAAs (human MUC1 [hMUC1] and HPV E7) tested. Vaccination with the Ad-sighMUC1/ecdCD40L vector suppressed the growth of hMUC1 antigen-positive tumor cells in 100% of the test mice that were previously anergic to the hMUC1 antigen. These data suggest that Ad-sig-TAA-ecd/ecdCD40L vector injections may be of value in treating the many epithelial malignancies in which TAA-like hMUC1 is overexpressed.
Tang
Yucheng
Y
Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, USA.
Zhang
Lixin
L
Yuan
Jing
J
Akbulut
Hakan
H
Maynard
Jonathan
J
Linton
Phyllis-Jean
PJ
Deisseroth
Albert
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics* / Q000276:immunology / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D017635:Clonal Anergy / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005822:Genetic Vectors / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018396:Mucin-1 / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D009856:Oncogene Proteins, Viral / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D027383:Papillomaviridae; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology
D000951:Antigens, Neoplasm; C515370:CCR7 protein, human; D019496:Cancer Vaccines; C515371:Ccr7 protein, mouse; D016207:Cytokines; C116055:MUC1 tandem repeat peptide; D018396:Mucin-1; D009856:Oncogene Proteins, Viral; D010446:Peptide Fragments; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand