IFN-GAMMA AND B7 AS COSTIMULATORS OF ANTITUMOR IMMUNE-RESPONSES

We transfected the mouse IFN-gamma and/or the mouse B7 (T cell costimu latory molecule) cDNAs into B16 melanoma cells to study the effects of local constitutive expression of these molecules on the tumorigenicit y and immunogenicity of this aggressive tumor. Cells expressing IFN-ga mma (B16.IFN-gamma), B7 (B16.B7), B7 and IFN-gamma (B16.IFN-gamma/B7), and parental cells were injected subcutaneously (s.c.) into syngeneic C57BL/6 mice to compare their in vivo growth. We report that IFN-gamm a secretion significantly reduced the tumorigenicity of B16 cells. The se effects were related to the direct action of secreted IFN-gamma sin ce i) in vivo injection of antiserum to IFN-gamma accelerated tumor gr owth, ii) development of tumor correlated with loss of IFN-gamma produ ction, and iii) B16.IFN-gamma cells were tumorigenic in IFN-II recepto r (IFN-gamma R) knockout mice, but not in parental mice. We propose th at immune mechanisms are being activated by IFN-gamma since i) immune effector cells were recruited to the injection site, ii) expression of MHC class I and class II antigens was increased on cells secreting IF N-gamma and, iii) B16.IFN-gamma tumors appeared earlier in athymic mic e than in immunocompetent mice. Since the in vivo growth of B16.IFN-ga mma cells was not completely abolished, we studied the effect of co-ex pression of IFN-gamma and the T cell costimulatory molecule B7 on the tumorigenicity of B16 cells. We report that B16.IFN-gamma/B7 cells, wh ich also express increased levels of MHC class I and class II molecule s as compared to parental cells, had a dramatically suppressed tumorig enicity, while B16 cells expressing the B7 molecule only (B16.B7) were as tumorigenic as the parental cells. B16.IFN-gamma/B7 cells induced specific immune responses since all of the protected mice were able to reject challenges with parental cells. Results indicate that co-expre ssion of two molecules which are involved in the activation of immune responses and in antigen presentation can influence the ability of the immune system to recognize and eliminate both transfected as well as parental tumor cell inocula and suggest that vaccines consisting of su ch cells may be used for the immunotherapy of cancer.