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

Alena Cristina Jaime-Ramirez, Bethany L. Mundy-Bosse, SriVidya 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 journalArticle

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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
Externally publishedYes

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Interleukin-12
Natural Killer Cells
Neoplasms
Cytokines
Therapeutics
Monokines
Apoptosis
T-Lymphocytes
Chemokine CCL5
Therapeutic Uses
Trastuzumab
Interleukin-1
Colon
Adenocarcinoma
Necrosis
Immunoglobulin G
Cell Proliferation
Lymphocytes
Growth

ASJC Scopus subject areas

  • Immunology

Cite this

Jaime-Ramirez, A. C., Mundy-Bosse, B. L., Kondadasula, S., Jones, N. B., Roda, J. M., Mani, A., ... Carson, W. E. (2011). IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production. Journal of Immunology, 186(6), 3401-3409. https://doi.org/10.4049/jimmunol.1000328

IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production. / Jaime-Ramirez, Alena Cristina; Mundy-Bosse, Bethany L.; Kondadasula, SriVidya; Jones, Natalie B.; Roda, Julie M.; Mani, Aruna; Parihar, Robin; Karpa, Volodymyr; Papenfuss, Tracey L.; LaPerle, Krista M.; Biller, Elizabeth; Lehman, Amy; Chaudhury, Abhik Ray; Jarjoura, David; Burry, Richard W.; Carson, William E.

In: Journal of Immunology, Vol. 186, No. 6, 15.03.2011, p. 3401-3409.

Research output: Contribution to journalArticle

Jaime-Ramirez, AC, Mundy-Bosse, BL, Kondadasula, S, Jones, NB, Roda, JM, Mani, A, Parihar, R, Karpa, V, Papenfuss, TL, LaPerle, KM, Biller, E, Lehman, A, Chaudhury, AR, Jarjoura, D, Burry, RW & Carson, WE 2011, 'IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production', Journal of Immunology, vol. 186, no. 6, pp. 3401-3409. https://doi.org/10.4049/jimmunol.1000328
Jaime-Ramirez AC, Mundy-Bosse BL, Kondadasula S, Jones NB, Roda JM, Mani A et al. IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production. Journal of Immunology. 2011 Mar 15;186(6):3401-3409. https://doi.org/10.4049/jimmunol.1000328
Jaime-Ramirez, Alena Cristina ; Mundy-Bosse, Bethany L. ; Kondadasula, SriVidya ; Jones, Natalie B. ; Roda, Julie M. ; Mani, Aruna ; Parihar, Robin ; Karpa, Volodymyr ; Papenfuss, Tracey L. ; LaPerle, Krista M. ; Biller, Elizabeth ; Lehman, Amy ; Chaudhury, Abhik Ray ; Jarjoura, David ; Burry, Richard W. ; Carson, William E. / IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production. In: Journal of Immunology. 2011 ; Vol. 186, No. 6. pp. 3401-3409.
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AU - Roda, Julie M.

AU - Mani, Aruna

AU - Parihar, Robin

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AU - Papenfuss, Tracey L.

AU - LaPerle, Krista M.

AU - Biller, Elizabeth

AU - Lehman, Amy

AU - Chaudhury, Abhik Ray

AU - Jarjoura, David

AU - Burry, Richard W.

AU - Carson, William E.

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N2 - 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.

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