Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells.
Tumor-derived α-fetoprotein impairs the differentiation and T cell stimulatory activity of human dendritic cells.
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DOI：
10.4049/jimmunol.1400725
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发表时间：
2014-12-01
期刊：
影响因子：
--
通讯作者：
Butterfield LH
中科院分区：
文献类型：
--
作者：
Pardee AD;Shi J;Butterfield LH
一些肿瘤衍生因子与癌症患者 DC 功能障碍有关。甲胎蛋白 (AFP) 是一种癌胎儿抗原，在产前发育异常和多种上皮癌（包括肝细胞癌 (HCC)）中高表达。在血清 AFP 水平高的 HCC 患者中，我们观察到与血清 AFP 水平低的患者和健康供体相比，髓系与浆细胞样循环 DC 的比率较低。为了测试 AFP 对 DC 体外分化的影响，在存在脐带血来源的正常 AFP (nAFP) 或 HCC 肿瘤来源的 AFP (tAFP) 的情况下培养健康供体的外周血单核细胞，并评估 DC 表型和功能。尽管 nAFP 和 tAFP 亚型仅在一种碳水化合物组上存在差异，但低（生理）水平的 tAFP（而非 nAFP）显着抑制 DC 分化。 tAFP 条件下的 DC 表达的 DC 成熟标志物水平降低，保留了单核细胞样形态，炎症介质的产生有限，并且未能诱导强大的 T 细胞增殖反应。机理研究表明，tAFP 的抑制活性取决于低分子量 (LMW) 物质的存在，该物质 i) 与 tAFP 共同纯化，并且 ii) 与肿瘤和非肿瘤细胞裂解物的 LMW 组分具有相同的功能。这些数据揭示了 tAFP 作为 LMW 分子的伴侣蛋白的独特能力，无论是内源性的还是自然界中普遍存在的，它们协同作用以损害 DC 的分化和功能。因此，拮抗 tAFP 调节特性的新治疗方法对于增强免疫力和改善临床结果至关重要。
Several tumor-derived factors have been implicated in DC dysfunction in cancer patients. Alpha-fetoprotein (AFP) is an oncofetal antigen that is highly expressed in abnormalities of prenatal development and several epithelial cancers, including hepatocellular carcinoma (HCC). In HCC patients exhibiting high levels of serum AFP, we have observed a lower ratio of myeloid-to-plasmacytoid circulating DC compared to patients with low serum AFP levels and healthy donors. To test the effect of AFP on DC differentiation in vitro, peripheral blood monocytes from healthy donors were cultured in the presence of cord blood-derived normal AFP (nAFP) or HCC tumor-derived AFP (tAFP), and DC phenotype and function was assessed. Although the nAFP and tAFP isoforms only differ at one carbohydrate group, low (physiological) levels of tAFP, but not nAFP, significantly inhibited DC differentiation. tAFP-conditioned DC expressed diminished levels of DC maturation markers, retained a monocyte-like morphology, exhibited limited production of inflammatory mediators, and failed to induce robust T cell proliferative responses. Mechanistic studies revealed that the suppressive activity of tAFP is dependent on the presence of low molecular weight (LMW) species that i) co-purify with tAFP, and ii) function equivalently to the LMW fractions of both tumor and non-tumor cell lysates. These data reveal the unique ability of tAFP to serve as a chaperone protein for LMW molecules, both endogenous and ubiquitous in nature, which function cooperatively to impair DC differentiation and function. Therefore, novel therapeutic approaches that antagonize the regulatory properties of tAFP will be critical to enhance immunity and improve clinical outcomes.
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影响因子：
24.5
作者：
Chew V;Chen J;Lee D;Loh E;Lee J;Lim KH;Weber A;Slankamenac K;Poon RT;Yang H;Ooi LL;Toh HC;Heikenwalder M;Ng IO;Nardin A;Abastado JP
通讯作者：
Abastado JP
影响因子：
8.8
作者：
Johnson PJ;Poon TC;Hjelm NM;Ho CS;Ho SK;Welby C;Stevenson D;Patel T;Parekh R;Townsend RR
通讯作者：
Townsend RR
影响因子：
11.5
作者：
Butterfield, LH;Ribas, A;Economou, JS
通讯作者：
Economou, JS
DOI：
10.1073/pnas.73.12.4645
发表时间：
1976-01-01
影响因子：
11.1
作者：
LESTER, EP;MILLER, JB;YACHNIN, S
通讯作者：
YACHNIN, S
影响因子：
3.9
作者：
Lee, WC;Wang, HC;Chen, MF
通讯作者：
Chen, MF