B7.1 expression eliminates tumor resistance to IL-12 gene therapy.
IL-12 gene therapy results in tumor regression in some, but not all, murine models. We hypothesized that expression of B7.1 on the tumor cell surface was necessary for IL-12-mediated tumor regression. In addition, we hypothesized that all cells must express B7.1 for this to be effective. To evaluate this hypothesis, tumor nodules were established in mice with either wild-type B16 melanoma or with B16 melanoma modified to express B7.1. IL-12 cDNA was transferred to the tumor by particle-mediated gene transfer. All tumors modified to express B7.1 regressed completely after IL-12 cDNA treatment. When the percent of B7.1-transfected B16 cells was decreased to 50%, no animals survived after treatment. Animals rendered tumor-free were then challenged with wild-type B16. Fifty percent of mice was protected from this tumor challenge. Expression of CD28 (the stimulatory B7.1 ligand) was significantly increased in both CD8(+) T cells and natural killer cell populations of mice rejecting tumor challenge compared to mice with tumor growth. These results suggest that the costimulatory molecule B7.1 is required for initial tumor sensitivity to IL-12 gene therapy and that protection from subsequent challenge with B7.1 (-) tumor is mediated by CD28(+) immune effector cells.
Department of Surgery, University of Wisconsin Hospitals and Clinics, Madison, USA.
C P
CP
Heise
F
F
Shi
M R
MR
Albertini
D M
DM
Mahvi
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism*; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D060908:CTLA-4 Antigen; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy; D018796:Immunoconjugates; D018664:Interleukin-12 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000378:metabolism; D008546:Melanoma, Experimental / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000473:pathology; D014162:Transfection
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D018664:Interleukin-12; D000069594:Abatacept