Irradiated NC adenocarcinoma cells transduced with both B7.1 and interleukin-2 induce CD4+-mediated rejection of established tumors.
Previous studies have shown that expression of the immune co-stimulator B7.1 reduces the tumorigenicity of some, but not all, malignant cell lines. However, B7.1-expressing tumor cells are not very effective in inducing the rejection of established tumors. This may in part be due to induction of anergy in the potentially reactive T cells. Previous studies have shown that IL-2 can reverse the anergic state both in vitro and in vivo. Therefore, we have examined the effect of retrovirus-mediated delivery and expression of murine B7.1 and interleukin-2 on tumor formation and rejection of established MHC class I+/II- NC adenocarcinomas. Neither the expression of B7.1 nor IL-2 alone had a significant effect on NC tumorigenicity. In contrast, combined expression of B7.1 and IL-2 substantially decreased the tumorigenicity of these cells in the immunecompetent syngeneic hosts. T-cell depletion studies show this to be dependent primarily on the activation of CD4+ cells. Furthermore, distant subcutaneous injection of irradiated NC/IL-2/B7.1 can induce, much more effectively than NC/B7.1 or NC/IL-2, the rejection of small NC tumors, and prevent the recurrence of large surgically resected tumors. Together, these results suggest that tumor cells genetically modified to express B7.1 and IL-2 can induce the immune-mediated rejection of established class II- tumors by a mechanism involving CD4+ cells.
Gaken
J A
JA
Department of Molecular Medicine, King's College School of Medicine & Dentistry, London, UK.
Hollingsworth
S J
SJ
Hirst
W J
WJ
Buggins
A G
AG
Galea-Lauri
J
J
Peakman
M
M
Kuiper
M
M
Patel
P
P
Towner
P
P
Patel
P M
PM
Collins
M K
MK
Mufti
G J
GJ
Farzaneh
F
F
Darling
D C
DC
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007223:Infant; D007376:Interleukin-2 / Q000276:immunology* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000628:therapy; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D014162:Transfection; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D007376:Interleukin-2