High DGK-α and Disabled MAPK Pathways Cause Dysfunction of Human Tumor-Infiltrating CD8+ T Cells That Is Reversible by Pharmacologic Intervention
High DGK-α and Disabled MAPK Pathways Cause Dysfunction of Human Tumor-Infiltrating CD8+ T Cells That Is Reversible by Pharmacologic Intervention
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DOI：
10.4049/jimmunol.1103028
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发表时间：
2012-06-15
影响因子：
4.4
通讯作者：
Noessner, Elfriede
中科院分区：
文献类型：
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作者：
Prinz, Petra U.;Mendler, Anna N.;Noessner, Elfriede
CD 8（+）肿瘤浸润性T细胞（CD 8-TILs）存在于多种类型的肿瘤中，包括人肾细胞癌。然而，肿瘤排斥很少发生，表明在肿瘤微环境中的功能活性有限。在这项研究中，我们记录了CD 8-TIL对CD 3刺激无反应，既不显示裂解活性，也不显示裂解颗粒胞吐作用，也不显示IFN-γ产生。从机制上讲，没有发现TCR近端信号分子（淋巴细胞特异性蛋白酪氨酸激酶，磷脂酶C γ）的缺陷。相反，远端TCR信号传导被抑制，因为TIL的T细胞显示出MAPK ERK的稳态磷酸化强烈降低，并且在刺激后不能增加ERK和JNK以及AKT和AKT客户蛋白（I κ B，GSK 3）的磷酸化。这些缺陷是肿瘤特异性的，因为在浸润非肿瘤肾区域的CD 8（+）T细胞（CD 8（+）非肿瘤肾浸润淋巴细胞; CD 8-NIL）中未观察到。与CD 8-NILs相比，二酰基甘油激酶-α（DGK-alpha）在CD 8-TILs中的表达更高，并且其抑制改善ERK磷酸化和溶解颗粒胞吐。在低剂量IL-2中培养TIL降低了DGK-alpha蛋白水平，增加了ERK的稳态磷酸化，改善了ERK和AKT的刺激诱导磷酸化，并允许更多的CD 8-TIL去活化并产生IFN-γ。此外，AKT客户分子p27 kip（一种抑制细胞周期的蛋白）的蛋白水平降低，而促进G1-S期转变的细胞周期蛋白E的蛋白水平升高。这些结果表明肿瘤造成的TIL缺陷是可逆的。DGK-alpha抑制和IL-2信号的提供可能是招募天然CD 8（+）T细胞参与抗肿瘤反应的策略，并可能有助于防止过继转移的T细胞失活，从而提高治疗效果。免疫学杂志，2012，188：5990-6000。
CD8(+) tumor-infiltrating T cells (CD8-TILs) are found in many types of tumors including human renal cell carcinoma. However, tumor rejection rarely occurs, suggesting limited functional activity in the tumor microenvironment. In this study, we document that CD8-TILs are unresponsive to CD3 stimulation, showing neither lytic activity, nor lytic granule exocytosis, nor IFN-gamma production. Mechanistically, no deficits in TCR proximal signaling molecules (lymphocyte-specific protein tyrosine kinase, phospholipase C gamma) were identified. In contrast, distal TCR signaling was suppressed, as T cells of TILs showed strongly reduced steady-state phosphorylation of the MAPK ERK and were unable to increase phosphorylation of ERK and JNK as well as AKT and AKT client proteins (I kappa B, GSK3) after stimulation. These deficits were tumor-specific as they were not observed in CD8(+) T cells infiltrating non-tumor kidney areas (CD8(+) non-tumor kidney-infiltrating lymphocytes; CD8-NILs). Diacylglycerol kinase-alpha (DGK-alpha) was more highly expressed in CD8-TILs compared with that in CD8-NILs, and its inhibition improved ERK phosphorylation and lytic granule exocytosis. Cultivation of TILs in low-dose IL-2 reduced DGK-alpha protein levels, increased steady-state phosphorylation of ERK, improved stimulation-induced phosphorylation of ERK and AKT, and allowed more CD8-TILs to degranulate and to produce IFN-gamma. Additionally, the protein level of the AKT client molecule p27kip, an inhibitory cell cycle protein, was reduced, whereas cyclin E, which promotes G1-S phase transition, was increased. These results indicate that the tumor-inflicted deficits of TILs are reversible. DGK-alpha inhibition and provision of IL-2 signals could be strategies to recruit the natural CD8(+) T cells to the anti-tumor response and may help prevent inactivation of adoptively transferred T cells thereby improving therapeutic efficacy. The Journal of Immunology, 2012, 188: 5990-6000.