Inhibitory effects of B cells on antitumor immunity
Inhibitory effects of B cells on antitumor immunity
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DOI：
10.1158/0008-5472.can-05-3766
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发表时间：
2006-08-01
期刊：
影响因子：
11.2
通讯作者：
Scott, Dorothy
中科院分区：
文献类型：
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作者：
Inoue, Satoshi;Leitner, Wolfgang W.;Scott, Dorothy
b细胞在抗肿瘤免疫中的作用尚不清楚。在这项研究中，我们利用Friend小鼠白血病病毒gag表达小鼠EL-4 （EL-4 gag）、D5小鼠黑色素瘤或MCA304小鼠肉瘤细胞，评估了B细胞在抗肿瘤免疫发展中的作用。为了筛选肿瘤对b细胞缺陷免疫环境的易感性，将C57BL/6[野生型（WT）]和b细胞敲除（BKO）小鼠的脾脏细胞与辐照过的肿瘤细胞一起体外培养。当细胞受到EL-4 gag或D5刺激（而不是MCA304肿瘤）时，与BKO培养相比，WT中CD8 T细胞和自然杀伤细胞的ifn - γ产生明显减少。ifn - γ的产生与肿瘤上CD40配体的表达相关，与B细胞产生白细胞介素-10 （IL-10）呈负相关。当与EL-4 gag或D5共培养时，分选的WT B细胞产生的IL-10比CD40敲除（CD40KO） B细胞多（但不包括MCA304）。BKO细胞产生的ifn - γ通过添加分选的原生WT B细胞（部分由CD40KO B细胞）或重组小鼠IL-10来减少。体内肿瘤进展反映在体外研究中，WT小鼠无法控制肿瘤生长，而EL-4 gag和D5肿瘤（但不是MCA304）在BKO小鼠中被消除。体内强大的抗肿瘤ctl仅在BKO肿瘤挑战小鼠中发展。我们的研究提供了第一个机制基础的概念，即B细胞消耗可以通过减少B细胞的IL-10产生来治疗性地增强对某些肿瘤的抗肿瘤免疫反应。
B-cell functions in antitumor immunity are not well understood. In this study, we evaluated the role of B cells in the development of antitumor immunity using Friend murine leukemia virus gag-expressing mouse EL-4 (EL-4 gag), D5 mouse melanoma, or MCA304 mouse sarcoma cells. To screen tumors for susceptibility to B-cell-deficient immune environments, spleen cells from naive C57BL/6 [wild-type (WT)] and B-cell knockout (BKO) mice were cultured with irradiated tumor cells in vitro. When cells were stimulated with EL-4 gag or D5 (but not MCA304 tumors), IFN-gamma production from CD8 T cells and natural killer cells was markedly decreased in WT compared with BKO cultures. IFN-gamma production was correlated with CD40 ligand expression on the tumor and inversely with interleukin-10 (IL-10) production by B cells. Sorted WT B cells produced more IL-10 than CD40 knockout (CD40KO) B cells when cocultured with EL-4 gag or D5 (but not MCA304). IFN-gamma production by BKO cells was reduced by the addition of sorted naive WT B cells (partially by CD40KO B cells) or recombinant mouse IL-10. In vivo tumor progression mirrored in vitro studies in that WT mice were unable to control tumor growth whereas EL-4 gag and D5 tumors (but not MCA304) were eliminated in BKO mice. Robust in vivo antitumor CTLs developed only in BKO tumor-challenged mice. Our studies provide the first mechanistic basis for the concept that B-cell depletion could therapeutically enhance antitumor immune responses to certain tumors by decreasing IL-10 production from B cells.