Department of Human Oncology, University of Wisconsin, Madison, WI 53705-2275, USA.
Immunology. 2011 Feb;132(2):226-39. doi: 10.1111/j.1365-2567.2010.03357.x. Epub 2010 Oct 13.
We studied the effectiveness of monoclonal anti-CD40 + cytosine-phosphate-guanosine-containing oligodeoxynucleotide 1826 (CpG-ODN) immunotherapy (IT) in mice treated with multidrug chemotherapy (CT) consisting of vincristine, cyclophosphamide and doxorubicin. Combining CT with IT led to synergistic anti-tumour effects in C57BL/6 mice with established B16 melanoma or 9464D neuroblastoma. CT suppressed the functions of T cells and natural killer (NK) cells, but primed naïve peritoneal macrophages (Mφ) to in vitro stimulation with lipopolysaccharide (LPS), resulting in augmented nitric oxide (NO) production. IT, given after CT, did not restore the responsiveness of T cells and NK cells, but further activated Mφ to secrete NO, interferon-γ (IFN-γ) and interleukin (IL)-12p40 and to suppress the proliferation of tumour cells in vitro. These functional changes were accompanied by immunophenotype alterations on Mφ, including the up-regulation of Gr-1. CD11b(+) F4/80(+) Mφ comprised the major population of B16 tumour-infiltrating leucocytes. CT + IT treatment up-regulated molecules associated with the M1 effector Mφ phenotype [CD40, CD80, CD86, major histocompatibility complex (MHC) class II, IFN-γ, tumour necrosis factor-α (TNF-α) and IL-12] and down-regulated molecules associated with the M2 inhibitory Mφ phenotype (IL-4Rα, B7-H1, IL-4 and IL-10) on the tumour-associated Mφ compared with untreated controls. Together, the results show that CT and anti-CD40 + CpG-ODN IT synergize in the induction of anti-tumour effects which are associated with the phenotypic repolarization of tumour-associated Mφ.
我们研究了多药化疗（CT）联合单克隆抗 CD40 + 胞嘧啶-磷酸-鸟嘌呤寡脱氧核苷酸 1826（CpG-ODN）免疫治疗（IT）在接受长春新碱、环磷酰胺和阿霉素治疗的小鼠中的疗效。CT 联合 IT 在 C57BL/6 小鼠中产生协同抗肿瘤作用，这些小鼠患有建立的 B16 黑色素瘤或 9464D 神经母细胞瘤。CT 抑制 T 细胞和自然杀伤（NK）细胞的功能，但使幼稚腹腔巨噬细胞（Mφ）对脂多糖（LPS）的体外刺激产生反应，导致一氧化氮（NO）产生增加。CT 后给予 IT 并不能恢复 T 细胞和 NK 细胞的反应性，但进一步激活 Mφ 分泌 NO、干扰素-γ（IFN-γ）和白细胞介素（IL）-12p40，并抑制肿瘤细胞在体外增殖。这些功能变化伴随着 Mφ 免疫表型的改变，包括 Gr-1 的上调。CD11b(+) F4/80(+) Mφ构成了 B16 肿瘤浸润白细胞的主要群体。CT + IT 治疗上调了与 M1 效应 Mφ表型相关的分子（CD40、CD80、CD86、主要组织相容性复合体（MHC）II 类、IFN-γ、肿瘤坏死因子-α（TNF-α）和 IL-12），并下调了与 M2 抑制 Mφ表型相关的分子（IL-4Rα、B7-H1、IL-4 和 IL-10）在与未治疗对照相比，肿瘤相关 Mφ。总之，结果表明 CT 和抗 CD40 + CpG-ODN IT 协同诱导抗肿瘤作用，与肿瘤相关 Mφ 的表型重极化相关。
