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Antitumor Effect of Interleukin (IL)-12 in the Absence of Endogenous IFN-

A Role for Intrinsic Tumor Immunogenicity and IL-15¹

Immunotherapy and Gene Therapy Unit, Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, 20133 Milan, Italy [G. G., C. C., E. G., M. P. C.]; Department of Experimental Medicine and Pathology, 2^nd Chair of Pathology, University of Rome "La Sapienza," 00161 Rome, Italy [A. S.]; and Department of Immunology and Bacteriology, University of Glasgow, Glasgow G11 6NT, United Kingdom [F. Y. L.]

IFN- knockout mice (GKO) rejected C26 colon carcinoma cells transduced to secrete interleukin(IL)-12 but do not reject similarly transduced TSA mammary adenocarcinoma (C26/12 and TSA/12 cells, respectively). To determine whether such difference could be because of a different tumor response to IFN-, we injected BALB/c mice with TSA, C26, and their IL-12-transduced counterparts rendered unresponsive to IFN- by stable transduction of a dominant negative (DN), truncated IFN- receptor chain. TSA/DN and C26/DN showed the same in vivo growth kinetics as parental cells, whereas coexpression of IL-12 induced rejection independent of tumor-cell responsiveness to IFN-. This suggests that the role of IFN- is primarily in activating the host immune response, which appears to depend on the intrinsic immunogenicity of the target tumor. C26 and TSA share a common tumor-associated antigen, yet C26 cells are more immunogenic than TSA. C26/12 expressed 10-fold higher levels of class I MHC molecules and induced higher CTL activity compared with TSA/12 cells in GKO mice. Moreover, whereas in GKO mice the TSA/12 tumor was associated with a greater number of infiltrating T cells, only those infiltrating C26/12 tumor expressed the activation marker OX40. The search for cytokine(s) that might contribute in determining the different T-cell response to these IL-12-transduced tumors in GKO mice revealed a role of IL-15. In situ hybridization showed IL-15 expression in C26/12 but not in TSA/12 tumors. In addition, injection of GKO mice with soluble IL-15 receptor- to block IL-15 expression prevented rejection of C26/12 cells. Together, the results suggest that in the absence of IFN-, IL-12 can exert antitumor activity through alternative mechanisms, depending on the tumor cell type and the availability of cytokines that can replace IFN- in sustaining T-cell functions.