title: IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production.
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-26(HER2/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-26(HER2/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.
authors.affiliation: Integrated Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Alena Cristina
authors.initials: AC
authors.lastname: Jaime-Ramirez
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Mundy-Bosse
authors.forename: SriVidya
authors.initials: S
authors.lastname: Kondadasula
authors.forename: Natalie B
authors.initials: NB
authors.lastname: Jones
authors.forename: Julie M
authors.initials: JM
authors.lastname: Roda
authors.forename: Aruna
authors.initials: A
authors.lastname: Mani
authors.forename: Robin
authors.initials: R
authors.lastname: Parihar
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Karpa
authors.forename: Tracey L
authors.initials: TL
authors.lastname: Papenfuss
authors.forename: Krista M
authors.initials: KM
authors.lastname: LaPerle
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Biller
authors.forename: Amy
authors.initials: A
authors.lastname: Lehman
authors.forename: Abhik Ray
authors.initials: AR
authors.lastname: Chaudhury
authors.forename: David
authors.initials: D
authors.lastname: Jarjoura
authors.forename: Richard W
authors.initials: RW
authors.lastname: Burry
authors.forename: William E
authors.initials: WE
authors.lastname: Carson
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000502:physiology; D018664:Interleukin-12 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D011897:Random Allocation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D000068878:Trastuzumab; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007371:Interferon-gamma; D018664:Interleukin-12; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human