Role of GM-CSF signaling in cell-based tumor immunization.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent adjuvant in cancer vaccination; however, the specific role of endogenous GM-CSF remains unknown. We performed cell-based vaccination in 2 tumor models. First, we vaccinated C57BL/6 mice lacking either GM-CSF, IL-5, or beta-common chain (betac), a receptor subunit essential for GM-CSF and IL-5 signaling, with melanoma cells engineered to produce GM-CSF. Tumor vaccination was effective in both GM-CSF(-/-) and IL-5(-/-) mice, showing that protective immunization is independent of both endogenous cytokines. However, all betac(-/-) animals developed tumor. Loss of tumor immunity in betac(-/-) mice does not reflect global impairment in cell-mediated immunity, as contact hypersensitivity reaction to haptens is unaltered. The importance of tumor cell-derived GM-CSF was highlighted by recruitment of dendritic cells at the vaccination site in wild-type, GM-CSF(-/-), and IL-5(-/-) but not in betac(-/-) mice. In the second model, vaccination with unmodified RENCA cells showed similar results with efficient immunization in BALB/c wild-type and GM-CSF(-/-), whereas all betac(-/-) animals died. Altogether, our results strongly suggest that although endogenous GM-CSF and IL-5 are not required to induce tumor immunity, signaling through betac receptor is critically needed for efficient cancer vaccination in both genetically modified GM-CSF-secreting tumor cells and a spontaneously immunogenic models.
Zarei
Shohreh
S
Oncology Division, Department of Internal Medicine, Geneva University Hospital and Geneva Medical School, 24 Rue Micheli-du-Crest, Geneva, Switzerland.
Schwenter
Frank
F
Luy
Patricia
P
Aurrand-Lions
Michel
M
Morel
Philippe
P
Kopf
Manfred
M
Dranoff
Glenn
G
Mach
Nicolas
N
D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor / Q000378:metabolism / Q000637:transplantation; D017077:Culture Media, Conditioned / Q000737:chemistry; D053648:Cytokine Receptor Common beta Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology; D003877:Dermatitis, Contact / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007279:Injections, Subcutaneous; D007377:Interleukin-3 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015848:Interleukin-5 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013045:Species Specificity; D014611:Vaccination / Q000379:methods
D019496:Cancer Vaccines; D017077:Culture Media, Conditioned; D053648:Cytokine Receptor Common beta Subunit; D016207:Cytokines; D007377:Interleukin-3; D015848:Interleukin-5; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor