IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production.
IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production.
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DOI：
10.4049/jimmunol.1000328
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发表时间：
2011-03-15
期刊：
影响因子：
--
通讯作者：
Carson WE 3rd
中科院分区：
文献类型：
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作者：
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 3rd
治疗性单抗的抗肿瘤作用可能依赖于表达免疫球蛋白受体的免疫效应细胞。IL-12是一种刺激NK细胞和T细胞产生干扰素-γ的细胞因子。我们推测，IL-12与小鼠抗HER2/neu单抗(4D5)联合应用将增强FCR依赖的免疫机制，从而有助于其抗肿瘤活性。与单独使用IL-12、4D5或μ相比，每周三次的IL-12(1 PBS G)和4D5(1 mg/kg)治疗显著抑制了BALB/c小鼠中表达人HER2的小鼠结肠腺癌(CT-26HER2/neu)的生长。联合治疗与干扰素-γ、干扰素-γ诱导的单核细胞因子和RANTES的循环水平升高有关。对干扰素-γ缺陷小鼠的实验表明，这种细胞因子是观察到的IL-12加4D5治疗抗肿瘤效果所必需的。免疫细胞耗竭实验表明，NK细胞(而不是CD4+或CD8+T细胞)介导了该治疗组合的抗肿瘤作用。曲妥珠单抗联合IL-12治疗HER2/neu阳性肿瘤可诱导肿瘤坏死，但不影响肿瘤增殖、细胞凋亡、血管生成和淋巴细胞浸润。对CT-26HER2/neu肿瘤细胞的体外实验表明，干扰素-γ诱导了细胞内信号，但不抑制细胞增殖或诱导细胞凋亡。综上所述，这些数据表明，曲妥珠单抗和IL-12联合治疗的肿瘤消退是通过NK细胞产生干扰素-γ介导的，并为NK细胞激活细胞因子与治疗性单抗联合应用提供了理论基础。
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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DOI：
10.1158/1078-0432.ccr-10-0735
发表时间：
2010-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cho D;Shook DR;Shimasaki N;Chang YH;Fujisaki H;Campana D
通讯作者：
Campana D
影响因子：
64.5
作者：
DREBIN, JA;LINK, VC;GREENE, MI
通讯作者：
GREENE, MI
影响因子：
56.9
作者：
Chin, YE;Kitagawa, M;Fu, XY
通讯作者：
Fu, XY
影响因子：
2.2
作者：
LIEBERMAN, MD;SIGAL, RK;DALY, JM
通讯作者：
DALY, JM
影响因子：
30.5
作者：
Eisenring, Maya;vom Berg, Johannes;Becher, Burkhard
通讯作者：
Becher, Burkhard