Document Detail


IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production.
MedLine Citation:
PMID:  21321106     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-02-14
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  186     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-03     Completed Date:  2011-05-26     Revised Date:  2014-09-24    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3401-9     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / immunology,  pathology,  therapy*
Animals
Antibodies, Monoclonal / therapeutic use*
Antibodies, Monoclonal, Humanized
Antineoplastic Agents / therapeutic use*
Colonic Neoplasms / immunology,  pathology,  therapy*
Cytotoxicity Tests, Immunologic
Female
Interferon-gamma / biosynthesis*,  physiology
Interleukin-12 / therapeutic use*
Killer Cells, Natural / immunology*,  metabolism,  pathology
Mice
Mice, Inbred BALB C
Random Allocation
Receptor, erbB-2 / immunology
Up-Regulation / immunology
Grant Support
ID/Acronym/Agency:
K01 RR022198/RR/NCRR NIH HHS; K24 CA93670/CA/NCI NIH HHS; P01 CA95426/CA/NCI NIH HHS; P30 CA016058/CA/NCI NIH HHS; P30 CA16058/CA/NCI NIH HHS; R21 CA092286/CA/NCI NIH HHS; T32 CA90338-27/CA/NCI NIH HHS; T32 GM068412/GM/NIGMS NIH HHS; UL1 RR025755/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Antineoplastic Agents; 187348-17-0/Interleukin-12; 82115-62-6/Interferon-gamma; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Receptor, erbB-2; P188ANX8CK/trastuzumab
Comments/Corrections

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