Centre Léon Bérard, F-69000 Lyon, France.
Cancer Res. 2011 Oct 1;71(19):6143-52. doi: 10.1158/0008-5472.CAN-11-0573. Epub 2011 Aug 18.
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-α, IFN-γ, and interleukin (IL)-1β], 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-1β and TNF-α are key players as monocyte depletion or neutralization of these cytokines attenuated secretion of CCL22. However, when purified monocytes were used, exogenous human IFN-γ was also required to generate this response suggesting a role for IFN-γ-producing cells within PBMCs. In this setting, we found that human IFN-γ 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-γ secretion, which in turn associates with monocyte-derived IL-1β and TNF-α 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.
在乳腺癌中，CCL22 招募调节性 T 细胞（Treg）进入淋巴聚集物似乎会对患者的生存产生负面影响。然而，这一过程的潜在机制（可能在实体瘤中具有更广泛的意义）尚未被描述。在这项研究中，我们确定了 CCL22 在肿瘤细胞中的产生是如何被控制的。在人乳腺癌细胞系中，CCL22 以低基础水平分泌，而在炎症信号[TNF-α、IFN-γ和白细胞介素（IL）-1β]的刺激下强烈增加，与 CCL17 形成对比。原发性乳腺癌和 CD45+浸润免疫细胞似乎共同作用以驱动 CCL22 的分泌，这在乳腺癌细胞系和外周血单核细胞（PBMC）或其上清液的共培养中表现得很明显。我们确定单核细胞衍生的 IL-1β和 TNF-α是关键因素，因为单核细胞耗竭或这些细胞因子的中和减弱了 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 内的 IFN-γ产生细胞发挥了作用。在这种情况下，我们发现人 IFN-γ可以被添加物（i）IL-2 或 K562 激活的自然杀伤（NK）细胞或（ii）在 MHC 类 I 抗体存在下的静止 NK 细胞替代。总的来说，我们的结果表明 NK 细胞和肿瘤细胞之间存在对话，导致 IFN-γ的分泌，这反过来又与单核细胞衍生的 IL-1β和 TNF-α一起驱动肿瘤细胞产生 CCL22，并随后招募 Treg。作为对原发性乳腺癌中这一结论的一个验证，我们表明 NK 细胞和巨噬细胞往往在肿瘤内聚集。总之，我们的研究结果表明，在肿瘤发生的早期，先天效应器（单核细胞和 NK 细胞）检测到肿瘤细胞，这对 CCL22 的分泌产生了选择，从而招募 Treg 来逃避这种早期的抗肿瘤免疫反应。
