In vivo characterization of the inflammatory infiltrate and apoptotic status in imiquimod-treated basal cell carcinoma
In vivo characterization of the inflammatory infiltrate and apoptotic status in imiquimod-treated basal cell carcinoma
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DOI：
10.1111/j.1365-4632.2009.03916.x
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发表时间：
2009-03-01
影响因子：
3.6
通讯作者：
Massi, Daniela
中科院分区：
文献类型：
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作者：
De Giorgi, Vincenzo;Salvini, Camilla;Massi, Daniela
咪喹莫特用于治疗基底细胞癌(BCC)已被证明在很大程度上是成功的，导致肿瘤消退；然而，确切的细胞机制尚未完全阐明。测量咪喹莫特治疗前后BCC患者肿瘤微环境的形态变化和皮肤活检组织中的细胞凋亡标志物。在这项开放的研究中，11例BCC患者在咪喹莫特治疗前后的皮肤活检进行了评估：(1)肿瘤微环境的形态变化，特别是肿瘤周围炎症细胞的免疫表型；和(Ii)细胞凋亡的标志物，包括死亡受体的表达。咪喹莫特治疗诱导了单核炎症反应的显著增加。在大多数病例中，细胞浸润物主要由CD3(+)/CD4(+)T细胞组成，提示效应反应是由CD3(+)/CD4(+)淋巴细胞介导的，并有少量的细胞毒和自然杀伤(NK)成分。细胞毒性CD3(+)/CD8(+)T细胞数量也有所增加。咪喹莫特治疗与CD20(+)B细胞显著增加有关，而在肿瘤周围或肿瘤内的单核巨噬细胞来源(CD68(+))细胞的增强不明显。这一发现表明，巨噬细胞在咪喹莫特诱导的反应中起着很小的作用，或者这些细胞的募集与时间和剂量有关。咪喹莫特治疗减少了表皮中CD1a(+)的朗格汉斯细胞，增加了肿瘤聚集区中CD1a(+)树突状细胞的数量。咪喹莫特降低了BCC细胞中Bc1-2的表达，但对Bax、Fas/FasL和P53的表达无影响。我们的结果支持了咪喹莫特治疗BCC的作用部分是CD3(+)/CD4(+)淋巴样细胞介导的促炎作用的结果，以及与降低Bc1-2表达相关的促凋亡作用的结果。
Imiquimod use in the treatment of basal cell carcinoma (BCC) has proven to be successful in a large percentage of cases, inducing tumor regression; however, the exact cellular mechanism has not been fully clarified.To measure the morphological changes in the tumor microenvironment and the markers of apoptosis in skin biopsies from patients with BCC before and after imiquimod treatment.In this open label study, skin biopsies obtained from 11 patients with BCC were evaluated before and after imiquimod treatment for: (i) morphological changes in the tumor microenvironment, with specific emphasis on the immunophenotype of inflammatory cells around the tumor; and (ii) markers of apoptosis, including expression of death receptors.Imiquimod treatment induced a significant increase in the mononuclear inflammatory response. In the majority of cases, the cellular infiltrate was predominantly composed of CD3(+)/CD4(+) T cells, suggesting that the effector response is mediated by CD3(+)/CD4(+) lymphocytes, with a minor cytotoxic and natural killer (NK) component. An increase in the cytotoxic CD3(+)/CD8(+) T-cell population was also observed. Imiquimod treatment was associated with a marked increased in CD20(+) B cells, and a less pronounced enhancement in cells of monocyte-macrophage origin (CD68(+)) surrounding, or within, the tumor. This finding indicates either that macrophages play a minor role in the imiquimod-induced response, or the recruitment of these cells is related to time and dose. Imiquimod treatment decreased CD1A(+) Langerhans cells in the epidermis and increased the number of CD1A(+) dendritic cells within the tumor aggregates. Imiquimod reduced Bcl-2 expression, but no difference was found in Bax, Fas/FasL, and p53 expression in BCC cells.Our results support the hypothesis that imiquimod activity in the treatment of BCC is partly a result of a pro-inflammatory action mediated by CD3(+)/CD4(+) lymphoid cells and of a pro-apoptotic activity associated with decreased Bcl-2 expression.