Bypassing tumor-associated immune suppression with recombinant adenovirus constructs expressing membrane bound or secreted GITR-L.
Recent evidence has resurrected the concept of specialized populations of T lymphocytes that are able to suppress an antigen-specific immune response. T-regulatory cells (T-reg) have been characterized as CD4+ CD25+ T cells. Previous reports describing differential gene expression analysis have shown that the glucocorticoid-induced tumor necrosis family receptor family-related gene (GITR) is upregulated in these cells. Furthermore, antibodies specific for GITR have been shown to inhibit the T-suppressor function of CD4+ CD25+ T-reg. The ligands for both mouse and human GITR have been cloned recently. We have inserted the sequences for natural, membrane-bound GITR-ligand (GITR-L) and a truncated secreted form of GITR-L (GITR-Lsol) into the adenovirus-5 genome. Coculture experiments show that cells infected with Ad-GITR-L and supernatants from cells infected with Ad-GITR-Lsol can increase the proliferation of both CD4+ CD25- and CD8+ T cells in response to anti-CD3 stimulation, in the presence, as well as in the absence, of CD4+ CD25+ T cells. The virus constructs were injected into growing B16 melanoma tumors. Ad-GITR-L was shown to attract infiltration with both CD4+ and CD8+ T cells. Both constructs were shown to inhibit tumor growth.
Molecular Immunology Laboratory, Transgene SA, Strasbourg 67082, France. calmels@transgene.fr
Bastien
B
Calmels
Stéphane
S
Paul
Nicolas
N
Futin
Catherine
C
Ledoux
Fabienne
F
Stoeckel
Bruce
B
Acres
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D015704:CD4 Antigens / Q000032:analysis*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D007165:Immunosuppression Therapy; D008024:Ligands; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D048069:Tumor Necrosis Factors
D018106:CD28 Antigens; D015704:CD4 Antigens; D002352:Carrier Proteins; D008024:Ligands; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors