Reduced efficacy of allogeneic versus syngeneic fibroblasts modified to secrete cytokines as a tumor vaccine adjuvant.
We examined the relative efficacy of allogeneic versus syngeneic fibroblasts admixed with tumor cells as a vaccine to induce antitumor T-cell reactivity. Allogeneic (3T3) or syngeneic (BLK) fibroblasts transfected to secrete equivalent amounts of GM-CSF were admixed with either D5 melanoma or MCA 207 sarcoma and inoculated s.c. into the flanks of C57BL/6 mice. Vaccine-primed lymph node (LN) cells were examined for in vivo antitumor reactivity in an adoptive transfer model. At fibroblast: tumor cell ratios of < or=1, allogeneic and syngeneic granulocyte macrophage colony-stimulating factor-secreting fibroblasts enhanced T-cell reactivity to tumor cells. However, at ratios of 2.4, the adjuvant effect induced by granulocyte macrophage colony-stimulating factor was not evident. Instead, we observed increased alloreactivity of primed LN cells against 3T3 targets as assessed by cytotoxicity and cytokine release assays, which was not observed with syngeneic fibroblasts. Moreover, with increasing numbers of allogeneic fibroblasts, there was a skewing of the T-cell Vbeta repertoire. These latter cells responded to tumor stimulation with the release of greater amounts of interleukin 10, which may account for the diminished antitumor reactivity observed in vivo. Allogeneic fibroblasts transduced to secrete interleukin 2 or IFN-gamma also induced diminished tumor reactivity of primed LN cells. Syngeneic fibroblasts are superior to allogeneic fibroblasts as vehicles to deliver cytokines in tumor vaccines.
Aruga
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Division of Surgical Oncology, University of Michigan, Ann Arbor 48109, USA.
Aruga
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Chang
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D016475:3T3 Cells; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000494:pharmacology; D008198:Lymph Nodes / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008815:Mice, Inbred Strains; D012513:Sarcoma, Experimental / Q000276:immunology / Q000517:prevention & control; D014162:Transfection; D014184:Transplantation, Homologous / Q000276:immunology*; D014185:Transplantation, Isogeneic / Q000276:immunology*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D007376:Interleukin-2; D016753:Interleukin-10; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor