探討酪胺酸激酶抑制劑對巨噬細胞的影響

Abstract

表皮生長因子受體為一種重要的癌症治療標的，而目前已開發出許多代的表皮生長因子受體-酪胺酸激酶抑制劑(EGFR-TKI)來治療非小細胞肺癌。雖然這類藥物能有效治療癌症，但是有報導指出使用表皮生長因子受體-酪胺酸激酶抑制劑會顯著提升非小細胞肺癌患者受到細菌感染的風險。然而至今仍未有人探討表皮生長因子受體酪胺酸激酶抑制劑對先天免疫的影響。在本篇論文中我探討第二代和第三代表皮生長因子受體-酪胺酸激酶抑制劑是否會影響先天免疫反應。結果顯示表皮生長因子受體-酪胺酸激酶抑制劑會抑制人類單核球細胞株THP-1分化成巨噬細胞的能力，同時使表皮生長因子受體酪胺酸激酶的磷酸化、細胞的貼附能力、移動能力、吞噬能力受到抑制。此外表皮生長因子缺陷會抑制THP-1分化、細胞移動性以及吞噬能力。這表示表皮生長因子受體-酪胺酸激酶抑制劑會透過抑制表皮生長因子酪胺酸激酶的磷酸化，造成單核球分化延遲。而在老鼠的骨髓巨噬細胞及腹腔巨噬細胞也得到了類似的結果。有服用表皮生長因子受體-酪胺酸激酶抑制劑的老鼠在接受巰基乙酸(thioglycollate)誘發發炎反應時，受到吸引的單核球會減少，並且延遲分化成巨噬細胞。這些結果顯示表皮生長因子受體-酪胺酸激酶抑制劑會抑制單核球分化成巨噬細胞並且降低先天免疫反應。

Epidermal growth factor receptor (EGFR) is one of the important therapeutic targets in human cancer and several EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed for the treatment of non-small cell lung carcinoma (NSCLC). Although EGFR-TKIs are generally effective on cancer therapy, it has been reported that EGFR-TKIs are with a risk of infectious events in NSCLC patients. However, how EGFR-TKIs affect immunity is still elusive. In this study, I investigated if a second-generation EGFR-TKI1 and a third-generation EGFR-TKI2 could alter innate immunity. The results showed that both EGFR-TKIs could significantly reduce the differentiation of human monocyte THP-1 cells into macrophages, which was concurrent with suppression of EGFR phosphorylation, the cell adherent, motility and phagocytosis. Moreover, EGFR silencing reduced THP-1 cell differentiation, motility, and phagocytosis. The results suggest that EGFR-TKIs can retard macrophage differentiation via inhibition of EGFR. Similar results of EGFR-TKI-inhibited macrophage differentiation and function were also obtained from bone marrow-derived macrophage (BMDM) and peritoneal macrophages. Moreover, EGFR-TKIs reduced the monocyte recruitment and monocyte-to-macrophage differentiation after thioglycollate induction. The results together indicate that EGFR-TKIs have inhibitory effects on the innate immunity via retarding monocyte-macrophage differentiation.