Antitumor effect of interleukin (IL)-12 in the absence of endogenous IFN-γ: A role for intrinsic tumor immunogenicity and IL-15

Giorgia Gri, Claudia Chiodoni, Elena Gallo, Antonella Stoppacciaro, Foo Y. Liew, Mario P. Colombo

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4390-4397
Number of pages8
JournalCancer Research
Volume62
Issue number15
StatePublished - Aug 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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