title: Antigens and cytokine genes in antitumor vaccines: the importance of the temporal delivery sequence in antitumor signals.
abstract: Studies against cancer, including clinical trials, have shown that a correct activation of the immune system can lead to tumor rejection whereas incorrect signaling results in no positive effects or even anergy. We have worked assuming that two signals, GM-CSF (granulocyte and macrophage colony-stimulating factor) and tumor antigens are necessary to mediate an antitumor effective response. To study which is the ideal temporal sequence for their administration, we have used a murine model of antimelanoma vaccine employing whole B16 tumor cells or their membrane protein antigens (TMPs) in combination with gm-csf transfer before or after the antigen delivery. Our results show that: (i) When gm-csf tisular transfection is performed before TMP delivery, a tumor growth inhibition is observed, but with a limit effect when administering high antigen doses; in contrast, when signals are inverted, the limited effect is lost and greater antitumor efficacy is obtained. (ii) A similar behavior, but with stronger positive results, is observed employing gm-csf transfection and whole tumor cells as antigens. While negative results are obtained with gm-csf before cells, the best results (total survival of treated mice) are obtained when GM-CSF is administered in transfected cells. We conclude that optimal antitumoral response can be obtained when the antigen signal is given before (or simultaneous with) GM-CSF production, while the inversion of the signals could result in the undesired inhibition or anergy of the immune response.
authors.affiliation: Gene Therapy Group, Department of Pharmacology, Faculty of Medicine, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain. mariajoseherrero@ono.com
authors.forename: María José
authors.initials: MJ
authors.lastname: Herrero
authors.forename: Rafael
authors.initials: R
authors.lastname: Botella
authors.forename: Francisco
authors.initials: F
authors.lastname: Dasí
authors.forename: Rosa
authors.initials: R
authors.lastname: Algás
authors.forename: María
authors.initials: M
authors.lastname: Sánchez
authors.forename: Salvador F
authors.initials: SF
authors.lastname: Aliño
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology* / Q000502:physiology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology / Q000502:physiology; D016219:Immunotherapy, Adoptive; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor