IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production

Alena Cristina Jaime-Ramirez, Bethany L. Mundy-Bosse, Sri Vidya Kondadasula, Natalie B. Jones, Julie M. Roda, Aruna Mani, Robin Parihar, Volodymyr Karpa, Tracey L. Papenfuss, Krista M. LaPerle, Elizabeth Biller, Amy Lehman, Abhik Ray Chaudhury, David Jarjoura, Richard W. Burry, William E. Carson

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

The antitumor effects of therapeutic mAbs may depend on immune effector cells that express FcRs for IgG. IL-12 is a cytokine that stimulates IFN-γ production from NK cells and T cells. We hypothesized that coadministration of IL-12 with a murine anti-HER2/ neu mAb (4D5) would enhance the FcR-dependent immune mechanisms that contribute to its antitumor activity. Thrice-weekly therapy with IL-12 (1 μg) and 4D5 (1 mg/kg) significantly suppressed the growth of a murine colon adenocarcinoma that was engineered to express human HER2 (CT-26HER2/neu) in BALB/c mice compared with the result of therapy with IL-12, 4D5, or PBS alone. Combination therapy was associated with increased circulating levels of IFN-γ, monokine induced by IFN-γ, and RANTES. Experiments with IFN-γ-deficient mice demonstrated that this cytokine was necessary for the observed antitumor effects of therapy with IL-12 plus 4D5. Immune cell depletion experiments showed that NK cells (but not CD4+ or CD8+ T cells) mediated the antitumor effects of this treatment combination. Therapy of HER2/neu-positive tumors with trastuzumab plus IL-12 induced tumor necrosis but did not affect tumor proliferation, apoptosis, vascularity, or lymphocyte infiltration. In vitro experiments with CT-26HER2/neu tumor cells revealed that IFN-γ induced an intracellular signal but did not inhibit cellular proliferation or induce apoptosis. Taken together, these data suggest that tumor regression in response to trastuzumab plus IL-12 is mediated through NK cell IFN-γ production and provide a rationale for the coadministration of NK cell-activating cytokines with therapeutic mAbs.

Original languageEnglish (US)
Pages (from-to)3401-3409
Number of pages9
JournalJournal of Immunology
Volume186
Issue number6
DOIs
StatePublished - Mar 15 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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