TY - JOUR
T1 - Antitumor effect of interleukin (IL)-12 in the absence of endogenous IFN-γ
T2 - A role for intrinsic tumor immunogenicity and IL-15
AU - Gri, Giorgia
AU - Chiodoni, Claudia
AU - Gallo, Elena
AU - Stoppacciaro, Antonella
AU - Liew, Foo Y.
AU - Colombo, Mario P.
PY - 2002/8/1
Y1 - 2002/8/1
N2 - IFN-γ 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-γ, we injected BALB/c mice with TSA, C26, and their IL-12-transduced counterparts rendered unresponsive to IFN-γ by stable transduction of a dominant negative (DN), truncated IFN-γ receptor a 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-γ. This suggests that the role of IFN-γ 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-α to block IL-15 expression prevented rejection of C26/12 cells. Together, the results suggest that in the absence of IFN-γ, IL-12 can exert antitumor activity through alternative mechanisms, depending on the tumor cell type and the availability of cytokines that can replace IFN-γ in sustaining T-cell functions.
AB - IFN-γ 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-γ, we injected BALB/c mice with TSA, C26, and their IL-12-transduced counterparts rendered unresponsive to IFN-γ by stable transduction of a dominant negative (DN), truncated IFN-γ receptor a 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-γ. This suggests that the role of IFN-γ 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-α to block IL-15 expression prevented rejection of C26/12 cells. Together, the results suggest that in the absence of IFN-γ, IL-12 can exert antitumor activity through alternative mechanisms, depending on the tumor cell type and the availability of cytokines that can replace IFN-γ in sustaining T-cell functions.
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M3 - Article
C2 - 12154045
AN - SCOPUS:0036682375
SN - 0008-5472
VL - 62
SP - 4390
EP - 4397
JO - Cancer Research
JF - Cancer Research
IS - 15
ER -