Antigens and cytokine genes in antitumor vaccines: the importance of the temporal delivery sequence in antitumor signals.
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.
Herrero
María José
MJ
Gene Therapy Group, Department of Pharmacology, Faculty of Medicine, University of Valencia, Av. Blasco Ibáñez 15, 46010 Valencia, Spain. mariajoseherrero@ono.com
Botella
Rafael
R
Dasí
Francisco
F
Algás
Rosa
R
Sánchez
María
M
Aliño
Salvador F
SF
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
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D016178:Granulocyte-Macrophage Colony-Stimulating Factor