Early Detection of Tumor Cells by Innate Immune Cells Leads to Treg Recruitment through CCL22 Production by Tumor Cells
Early Detection of Tumor Cells by Innate Immune Cells Leads to Treg Recruitment through CCL22 Production by Tumor Cells
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DOI：
10.1158/0008-5472.can-11-0573
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发表时间：
2011-10-01
期刊：
影响因子：
11.2
通讯作者：
Menetrier-Caux, Christine
中科院分区：
文献类型：
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作者：
Faget, Julien;Biota, Cathy;Menetrier-Caux, Christine
在乳腺癌中，CCL22将调节性T细胞（T - reg）募集到淋巴聚集物内似乎对患者的生存产生负面影响。然而，支撑这一过程的机制（在实体瘤中可能具有更广泛的意义）尚未被描述。在这项研究中，我们确定了肿瘤细胞中CCL22的产生是如何被控制的。在人乳腺癌细胞系中，CCL22以较低的基础水平分泌，在炎症信号[TNF -α、IFN -γ和白细胞介素（IL）- 1β]的作用下分泌量显著增加，这与CCL17不同。原发性乳腺癌肿瘤和CD45⁺浸润免疫细胞似乎协同促进CCL22的分泌，这在乳腺癌细胞系与外周血单个核细胞（PBMC）或其上清液的共培养中清晰可见。我们确定单核细胞衍生的IL - 1β和TNF -α是关键因素，因为单核细胞的耗竭或这些细胞因子的中和会减弱CCL22的分泌。然而，当使用纯化的单核细胞时，还需要外源性人IFN -γ来产生这种反应，这表明PBMC中产生IFN -γ的细胞起作用。在这种情况下，我们发现可以通过添加（i）IL - 2或K562激活的自然杀伤（NK）细胞或（ii）在抗MHC I类抗体存在下的静息NK细胞来替代人IFN -γ。综上所述，我们的结果显示NK细胞和肿瘤细胞之间存在一种对话，导致IFN -γ分泌，而IFN -γ又与单核细胞衍生的IL - 1β和TNF -α相关联，从而驱动肿瘤细胞产生CCL22并随后募集T - reg。作为对原发性乳腺癌这一结论的一种验证，我们表明NK细胞和巨噬细胞倾向于在肿瘤内共定位。总之，我们的研究结果表明，在肿瘤发生的早期，先天效应细胞（单核细胞和NK细胞）对肿瘤细胞的检测促使选择CCL22分泌，从而募集T - reg以逃避这种早期的抗肿瘤免疫反应。《癌症研究》；71(19)；6143 - 52。（C）2011美国癌症研究协会。
In breast carcinomas, patient survival seems to be negatively affected by the recruitment of regulatory T cells (T-reg) within lymphoid aggregates by CCL22. However, the mechanisms underpinning this process, which may be of broader significance in solid tumors, have yet to be described. In this study, we determined how CCL22 production is controlled in tumor cells. In human breast carcinoma cell lines, CCL22 was secreted at low basal levels that were strongly increased in response to inflammatory signals [TNF-alpha, IFN-gamma, and interleukin (IL)-1 beta], contrasting with CCL17. Primary breast tumors and CD45(+) infiltrating immune cells appeared to cooperate in driving CCL22 secretion, as shown clearly in cocultures of breast tumor cell lines and peripheral blood mononuclear cells (PBMC) or their supernatants. We determined that monocyte-derived IL-1 beta and TNF-alpha are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFN-g was also required to generate this response suggesting a role for IFN-gamma-producing cells within PBMCs. In this setting, we found that human IFN-g could be replaced by the addition of (i) IL-2 or K562-activated natural killer (NK) cells or (ii) resting NK cells in the presence of anti-MHC class I antibody. Taken together, our results show a dialogue between NK and tumor cells leading to IFN-gamma secretion, which in turn associates with monocyte-derived IL-1 beta and TNF-alpha to drive production of CCL22 by tumor cells and subsequent recruitment of T-reg. As one validation of this conclusion in primary breast tumors, we showed that NK cells and macrophages tend to colocalize within tumors. In summary, our findings suggest that at early times during tumorigenesis, the detection of tumor cells by innate effectors (monocytes and NK cells) imposes a selection for CCL22 secretion that recruits T-reg to evade this early antitumor immune response. Cancer Res; 71(19); 6143-52. (C) 2011 AACR.