Fas 屬於腫瘤壞死因子 (Tumor necrosis factor, TNF) 受器家族的一員，並且與 Fas ligand (FasL) 結合誘發細胞凋亡 (apoptosis)。以往研究認為腫瘤細胞能透過細胞表面的 FasL 與腫瘤浸潤淋巴細胞 (tumor-infiltrating lymphocytes, TILs) 表面的 Fas 結合，造成這些浸潤細胞走向死亡。但是為何仍有許多腫瘤浸潤淋巴細胞並未因腫瘤上 FasL 的作用死亡而聚集在腫瘤組織內的原因並不清楚。本研究利用腫瘤細胞與免疫細胞共同培養的方式，模擬腫瘤內的特殊環境來探討腫瘤浸潤淋巴細胞受到 Fas 訊息所調控細胞凋亡的影響。當人類 Jurkat 細胞 (T 淋巴球細胞株) 與腦神經瘤細胞 (Glioma) 共同培養而在細胞直接的接觸下，Jurkat 細胞對於 CH-11 (agonistic anti-Fas Ab) 所誘發的細胞凋亡敏感程度會降低。共同培養的環境下，Jurkat 細胞表面 Fas 的表現量並未受到影響，並且凋亡中的細胞也不是因為腦神經瘤細胞的吞噬而減少。腫瘤細胞株 MCF-7 與 HepG2 並無法提供這種保護效果。Caspases 的活化與death-inducing signaling complex (DISC) 的形成，都會因為與腦神經瘤細胞共同培養而受到抑制。近來研究指出細胞間質 (extracellular matrix, ECM) 構成的微環境會影響細胞的訊息傳遞。利用抗體阻斷 β integrin 與 ECM 的作用可以去除共同培養提供的保護效果。透過 ECM 的作用會增加 Jurkat 細胞內 ERK1/2, p38 MAPK 與 Akt 的磷酸化。抑制 PI3K 活性會阻斷透過腦神經瘤細胞共同培養而降低 CH-11 所造成的細胞死亡、Bcl-xL 的切割以及 Bad 在 serine 136 位置的磷酸化。
我們進一步研究 Fas 訊號刺激這些 “已受到保護” 的 T 細胞在腫瘤免疫上可能扮演的角色。近來的研究證明，老鼠體內表現 FasL 的腫瘤會發現許多分泌 IL-17 的細胞並伴隨更多的嗜中性白血球 (neutrophil) 浸潤。IL-17 主要是由 CD4+ T 輔助細胞產生與許多自體免疫疾病及發炎相關的細胞激素。目前 FasL 如何引發 IL-17 表現的機制目前並不清楚。我們懷疑 Fas 訊號刺激腫瘤浸潤細胞產生 IL-17。結果發現利用 CH-11 刺激 PHA/IL-2 活化的周邊 CD4+ 與 CD8+ T 細胞，在沒有發生細胞死亡的情形下會刺激 T 細胞轉錄因子 RORγt 的表現，而並非 T-bet, GATA3 與 FOXP3。此外，Fas 訊號會刺激周邊 CD4+ T 細胞表現 Th-17 細胞相關的 IL-17A, IL-17F, IL-22 與 IL-26 的轉錄作用。CD8+ T 細胞則僅表現 IL-17A 與 IL-17F, 但不表現 IL-22 與 IL-26。利用 Z-IETD-FMK 抑制 caspase-8 的活性，會降低 Fas 訊息誘發 CD4+ T 細胞 ERK1/2 的磷酸化並進一步抑制 IL-22 與 IL-26 的轉錄。Fas 訊號所增強的 RORγt, IL-17A 與 IL-17F表現，以及 Stat3 的磷酸化都會在 caspase-1 抑制劑 Z-YVAD-FMK 的作用下受到抑制。綜合以上的結果，我們確認 Fas 訊號會啟動二種個別的訊號傳遞路徑誘導周邊 T 細胞表現 Th-17 細胞的特徵。一為透過 caspase-8 活化 ERK1/2 調控 IL-22 與 IL-26的轉錄。另一為透過 caspase-1 而增強的 Stat3 磷酸化，提高 RORγt 的表現並進一步誘導 T 細胞中 IL-17A 與 IL-17F 的表現。
綜合以上的證據顯示腫瘤細胞會透過活化浸潤細胞的 PI3K/Akt 磷酸激酶，抑制腫瘤浸潤淋巴細胞內 Fas 訊息所調控的細胞凋亡。這些死亡被抑制的腫瘤浸潤淋巴細胞受到 Fas 訊息的作用表現 IL-17 並吸引更多嗜中性白血球的浸潤。這些發現提供了一個新的想法，重新評估 Fas 訊息並非只引發細胞凋亡的作用，也會透過 MAPK 與 Stat3 訊息傳遞路徑誘導這些腫瘤浸潤淋巴細胞趨向表現Th-17 細胞的特徵，並參與在許多自體免疫疾病和發炎症狀的發病機制。

Fas is a member of tumor necrosis factor (TNF) receptor family and mediates apoptosis when engagement with Fas ligand (FasL). It has been demonstrated that FasL expressed on tumor cells would crosslink with Fas protein of tumor-infiltrating lymphocytes (TILs), causing them to undergo programmed cell death. However, the hypothesis of why FasL expression of tumor cells could not trigger TILs cell death even with the fact that numerous TILs accumulated in the proximity of tumor nodule is yet not clear. In this study, we have analyzed Fas-triggered apoptosis in T cells in contact with tumor cells, which resembles cell-to-cell interactions found in tumor cells. When human Fas-sensitivity Jurkat cells were co-cultured with glioma, the sensitivity of Fas-mediated apoptosis by CH-11 (agonistic anti-Fas monoclonal Ab) is diminished. Meanwhile, Fas expression of Jurkat cells is not reduced and the apoptotic body does not decreased by way of phagocytosis of glioma cells. In contrast, the tumor cell lines MCF-7 and HepG2 produced no such protective effect. Caspase activation and death-inducing signaling complex (DISC) were reduced when co-cultured with glioma. Recently it has become apparent that the microenvironment made up of the extracellular matrix (ECM) may affect cell signaling. While interrupting the β integrins-matrix interaction, it diminished the co-culture effect. Cell matrix contact enhanced the phosphorylation of ERK1/2, p38 MAPK and Akt in Jurkat cells. PI3K inhibitor completely abolished contact-associated protection on these tumor cells and in parallel restored Fas-induced Bcl-xL cleavage as well as decreasing the phosphorylation of Bad at serine 136.
We further studied the possible effect on these so called “been protected” T cells. Recently, IL-17-secreting cells have been found to be abundant in several murine FasL-expressing tumors and associated with intensive neutrophils infiltration. CD4+ T helper cells are the major producers of IL-17 and involved in the pathogenesis of many autoimmune diseases and inflammatory conditions. At the moment how FasL triggers the production of IL-17 is not well understood. We suspected that Fas signaling stimulated IL-17 production in those TILs. Upon Fas ligation by CH-11 under non-apoptotic conditions, the expression of transcription factor RORγt (a thymus-specific isoform of the retinoic acid receptor-related orphan receptor) was stimulated in PHA/IL-2-activated CD4+ and CD8+ T cells, but not those of T-bet, GATA3 and FOXP3. Fas signaling stimulated transcriptions of Th-17-related cytokines, including IL-17A, IL-17F, IL-22 and IL-26 in CD4+ T cells. CD8+ T cells expressed only IL-17A, IL-17F but not IL-22 and IL-26. Caspase-8 inhibitor Z-IETD-FMK diminished the effects of Fas-associated induction on the ERK1/2 phosphorylation and transcriptions of IL-22 and IL-26 in CD4+ T cells. In addition, the Fas signal-enhanced RORγt, IL-17A, and IL-17F, as well as the phosphorylated signal transducer and activator of transcription 3 (Stat3) were reduced by treatment with caspase-1 inhibitor Z-YVAD-FMK. On top of it, our studies identified two Fas signaling pathways favoring the Th-17 phenotype. One activates ERK1/2 via caspase-8 to stimulate the IL-22 and IL-26 transcription. The other enhances Stat3 via caspase-1, leading to elevate RORγt and subsequently IL-17A and IL-17F expression in T cells.
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