頭頸部鱗狀上皮細胞癌是一種具有局部復發和遠處轉移特性的侵襲性癌症。研究結果顯示，在順鉑(cisplatin)治療後的頭頸癌病患細胞程序死亡-配體1 (PD-L1)的表現量增加會導致其預後較差。化療所導致的頭頸癌細胞休眠以及腫瘤微環境的改變可能是造成化療後轉移復發的原因之一。因此，本篇的研究方向在於探討PD-L1是否參與化療後誘導的腫瘤休眠以及轉移復發。首先，釐清本身表皮生長因子受體(EGFR)過表達的頭頸癌細胞中PD-L1的功能與調控機轉，發現在EGF刺激下的頭頸癌細胞會透過ERK1/2和NF-κB的訊息傳遞路徑增加PD-L1的表現。EGF所誘導頭頸癌細胞PD-L1的表現，會參與調控其細胞爬行與轉移相關之基因表現。致弱PD-L1的表現可以抑制EGF所誘導頭頸癌細胞抗失巢凋亡的能力。為了探討化療後存活的頭頸癌細胞之作用機轉，建立cisplatin處理後存活的頭頸癌細胞HONE-1 CDDP-S系統。發現CDDP-S細胞生長速率下降且DEC2、NR2F1以及p27等休眠相關基因的表現量增加，表示其進入休眠狀態。此外，CDDP-S細胞具有PD-L1高表達的現象，以及在EGF的刺激下其敏感度增加，促使更高表現的PD-L1與EMT標的基因。從以上實驗結果推測，在休眠狀態的CDDP-S細胞中，PD-L1參與調控EGF所誘導的細胞爬行以及抗失巢凋亡的能力來促使癌轉移。將來或許可以使用合併EGFR抑制劑以及PD-L1阻斷劑的治療方式，降低化療後的頭頸癌腫瘤復發的可能性，有助於改善其預後不良的結果。

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with the properties of local recurrence and distant metastasis. Recently, it has been demonstrated that PD-L1 expression may be increased during cisplatin treatment, resulting in worse prognosis in HNSCC patients. After cessation of the therapy, the dormant cells may reactivation, resulting in tumor recurrence and development of chemotherapy-resistant cancer cells. In the other hand, the tumor microenvironment is one of the reasons for metastasis. Therefore, the aim of this study is to clarify the role of PD-L1 in chemotherapy-induced tumor dormancy and metastatic recurrence. The first, to clarify the mechanism involved in the regulation of PD-L1 expression in EGFR overexpression of HNSCC cell lines. We found that EGF induced PD-L1 expression through ERK1/2 and NF-κB pathways. In addition, PD-L1 regulated EGF-induced HNSCC cell migration and EMT markers. PD-L1 depletion repressed EGF-induced HNSCC anoikis resistance. To further analyze the role of PD-L1 in chemotherapy-induced tumor dormancy for HNSCC. We established HONE-1 CDDP-S cells and found proliferation rate of CDDP-S cells was slower than HONE-1 cells. Also, the expression of dormancy-associated genes DEC2, NR2F1, and p27 were increased, indicating that the formation of tumor dormancy was occurred in CDDP-S cells. The expression of PD-L1 was higher in CDDP-S cells, inducible PD-L1 and EMT phenotype were observed in the EGF-treated condition. The results indicate that PD-L1 may involve in EGF-promoted anoikis resistance and cell migration of CDDP-S cells. It also speculates that the combination of EGFR inhibitor and PD-L1 antibody may reduce the possibility of tumor recurrence after chemotherapy in HNSCC.

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