腫瘤組織的浸潤T細胞是癌症病人癒後的重要指標之一。臨床研究發現浸潤T細胞聚集在腫瘤細胞群外圍基質(peritumoral region)不是好的癒後指標，可能會減少細胞接觸式的腫瘤細胞毒殺效果。已有研究指出腫瘤會分泌細胞外基質(extracellular matrix, ECM)來阻止T細胞的浸潤。本篇研究指出腫瘤細胞產生的細胞外基質可以抑制T細胞移動穿透的能力。我們在transwell system中進行T細胞移動穿透腫瘤的單一細胞層與細胞外基質實驗。結果顯示周邊血T細胞和Jurkat與Molt-4人類T淋巴瘤細胞株在移動穿透腦瘤細胞株U-87MG、U-118MG，與U-373MG的單一細胞層或細胞外基質之數量，比穿透乳癌細胞株MCF-7與肝癌細胞株HepG2的單一細胞層或細胞外基質的數量少。根據曠時拍照觀察，我們將Jurkat T細胞在腫瘤細胞外基質上的形態分成圓形（round）、不平整形（rough），與類阿米巴原蟲形（amoeba-like）三種，結果發現減少了amoeba-like形態是穿透數量變少的主要原因。分析腫瘤細胞株的細胞外基質組成，發現腦瘤細胞株有tenascin-C的表現，但MCF7與HepG2卻沒有。利用核醣核酸干擾技術（RNA interferences）抑制腦瘤細胞株的tenascin-C表現，則可讓較多的T細胞移動穿透，且amoeba-like形態的細胞數量也增加。若外給tenascin-C，則可有效抑制T細胞對MCF-7與HepG2單一細胞層或細胞外基質的穿透量，且細胞產生amoeba-like形態的比例也會明顯下降。透過免疫螢光染色技術我們發現人類腦瘤組織有顯著的tenascin-C表現，且大部分CD3+ T細胞會聚集在腫瘤區域有很強的tenascin-C表現之邊界。我們也在tenascin-C過量表現的B16F10小鼠黑色素瘤模式發現類似的現象。此外tenascin-C也可以減少LPS引發小鼠背部皮下氣囊的白血球浸潤。我們進一步依序使用LY294002、U0126，與H-89抑制劑，發現Jurkat細胞的移動穿透是需要PI3K、ERK，與PKA的酵素活性。然而，Jurkat細胞在U-118MG單一細胞層或細胞外基質上，其ERK磷酸化的引發有延遲的現象。在U0126的作用下，確實會減少Jurkat細胞在MCF-7細胞外基質上的amoeba-like形態的產生。有趣的是Jurkat細胞在tenascin-C受抑制U-118MG的單一細胞層上，則其ERK磷酸化引發延遲的現象就會消失，且磷酸化的ERK會與聚合的細胞骨架F-actin共同位在amoeba-like形態的Jurkat細胞之移動前緣。綜合上述結果得知，腦瘤細胞的tenascin-C會使T細胞的amoeba-like形態減少而抑制T細胞的穿透移動，所以本研究提供了一個腫瘤透過細胞外基質來抑制免疫反應的新機制。

Infiltrating T lymphocyte in tumors is correlated with the cancer prognosis. Clinical data showed the accumulation of infiltrating T lymphocyte in peritumoral area is not good for the prognosis, which could reduce the efficiency of contact-dependent lysis of tumor cells. Tumor cells could secrete extracellular matrix (ECM) to impede T lymphocyte infiltration. In this study, we demonstrate that ECM produced by tumors can directly regulate T cell migration. We performed the transmigration of T cells through the tumor cell monolayers or tumor ECM in the transwell system. The result showed that the transmigration rates of primary T cells and lymphoma cell lines Jurkat and Molt-4 cells through the cell monolayers or ECM of glioma cell line U-87MG, U-118MG, and U373MG cells were consistently lower than that through the cell monolayers or ECM of breast cancer cell line MCF-7 and hepatoma cell line HepG2. According to timelapse microscopy observation, the morphological changes of Jurkat T cells on tumor ECM were classified into round, rough, and amoeba-like shape. The low transmigration rate of Jurkat T cells was mainly due to the reduction of ameba-like shape formation. By analyzing the componets of tumor ECM, we found the tenascin-C expression was only detected in glioma cell lines but not in MCF-7 and HepG2 cells. Knocking down the tenascin-C gene using the shRNA strategy converted glioma cells to a transmigration-permissive phenotype for T cell transmigration and ameba-like shape formation. Exogenous tenascin-C protein reduced the amoeba-like shape formation and transmigration of T cells through MCF-7 and HepG2 cell monolayers. By immunoflurosecent staining, we found that high level of tenascin-C was visualized in glioma tumor tissues. CD3+ T cells were detected in the boundary tumor area stained strong positive for tenascin-C. Similar phenomenon was also found in tenascin-C-overexpressed B16F10 tumor model. In addition, tenascin-C could reduce the LPS-induced leukocyte infiltration in air pouch of mouse model. Further, we found that kinase activites of PI3K, ERK, and PKA are required for the Jurkat cell transmigration by the treatments of LY294002, U0126, and H-89 inhibitors, respectively. However, Jurkat T cells showed delayed ERK activation when they were in contact with the cell monolayer or ECM of glioma cells as compared with those in contact with HepG2 and MCF-7 cells. Meanwhile, amoeba-like shape of Jurkat cells on MCF-7 ECM was recuded upon U0126 treatment. Interestingly, ERK activation was no more delayed when Jurkat cells contacted with the cell monolayer of tenascin-C-dowenregulated U-118MG cells. Besides, phospho-ERK was colocalized with polymerized F-actin at the leading edge of amoeba-like moving Jurkat. In conclusion, glioma cells can actively paralyze T cell migration by the expression of tenascin-C, representing a novel immune suppressive mechanism achieved through tumor ECM.

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