Therapeutic effect of Imiquimod enhanced ALA-PDT on cutaneous squamous cell carcinoma
Therapeutic effect of Imiquimod enhanced ALA-PDT on cutaneous squamous cell carcinoma
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咪喹莫特增强ALA-PDT治疗皮肤鳞癌的疗效
DOI：
10.1016/j.pdpdt.2018.07.010
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发表时间：
2018-09-01
影响因子：
3.3
通讯作者：
Zhang, Guolong
中科院分区：
文献类型：
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作者：
Bhatta, Anil Kumar;Wang, Peiru;Zhang, Guolong
背景：局部光动力学疗法（PDT）已被批准用于治疗光化性角化病、基底细胞癌和Bowen病。但目前不推荐用于皮肤浸润性鳞状细胞癌（SCC），因为局部应用的光敏剂渗透不足导致治疗反应差。咪喹莫特（imiquimod，IMQ）作为一种免疫调节剂和Toll样受体7（TLR7）激动剂，具有抗肿瘤活性。作为一种辅助治疗，它最近被认为是加强PDT的效果。方法：这是在体内实验进行的52 SCC植入小鼠模型。将小鼠随机分为四组：IMQ组、IMQ + PDT组、PDT组和对照组。IMQ + PDT治疗组用5% IMQ乳膏和ALA-PDT治疗3次。IMQ组仅给予5% IMQ乳膏。同样，PDT组小鼠仅接受ALA-PDT，对照组小鼠不接受治疗。通过肿瘤体积和数码照片比较各组的治疗效果。另外，对12只紫外线诱导的小鼠模型进行免疫组化标记、qPCR和细胞凋亡检测。在动物实验取得成功后，我们对两名唇和足浸润性CSCC患者进行了人体研究。每日外用5%咪喹莫特乳膏，间隔2周后进行ALA-PDT治疗。结果：IMQ + PDT联合治疗效果优于单纯IMQ或PDT。IMQ + PDT组IL-6、IL-8、IFN-α、CXCL9、CXCL10和TNF-α的表达在治疗后不同时间点均明显升高（P <0.05）。免疫组化染色结果显示，IMQ + PDT组与PDT组相比，CD4+细胞数量无明显差异，而CD8+细胞数量增加近一倍。IMQ + PDT组凋亡细胞数最多。结论：PDT联合咪喹莫特治疗浸润性cSCC有较好的疗效。IMQ + PDT组中凋亡细胞的最大数量可归因于该组中CD8 + T细胞数量的增加。IMQ + PDT组疗效增强的其他机制可能是由于本研究中检测的标志物表达增加。
Background: Topical photodynamic therapy (PDT) is approved treatment for actinic keratosis, basal cell carcinoma and Bowen's disease. But currently it is not recommended for invasive squamous cell carcinoma (SCC) of the skin because inadequate penetration of topically applied photosensitizers lead to poor treatment response. Imiquimod (IMQ) as an immune response modifier and Toll-like receptor 7 (TLR7) agonist, is known to exhibit antitumor activity. As an adjunct therapy, it is recently seen to enhance the effect of PDT.Method: This is an in vivo experiment performed on 52 SCC implanted mice model. The mice were equally divided into four groups: IMQ group, IMQ + PDT group, PDT group and control group. The mice in IMQ + PDT group were treated with 3 sessions of 5% IMQ cream and ALA-PDT. Mice in IMQ group received only 5% IMQ cream. Similarly, mice in PDT group received only ALA-PDT and control mice received no treatment. The treatment efficacy was compared among these groups via tumor volume and digital photographs. In addition, immunohistochemical (IHC) markers, q PCR and detection of apoptosis were studied on 12 UV induced mice model. After successful result of this animal experiment, we performed human study on two patients with invasive cSCC on lips and foot. The patients were treated with daily application of 5% imiquimod cream and ALA-PDT at 2 weeks interval. Treatment response was assessed via clinical examination, digital photographs and dermoscopy findings.Results: The study demonstrated that combination approach of IMQ + PDT has better effect than IMQ alone or PDT alone. It also showed increased expression of IL-6, IL-8, IFN-alpha, CXCL9, CXCL10 and TNF-alpha in IMQ + PDT group but at different time points following treatment (P < 0.05). IHC staining showed that the number of CD4 + cells was similar in IMQ + PDT and PDT groups but CD8 + cells was almost double in IMQ + PDT group when compared to PDT group. In addition, the number of apoptotic cell was maximum in IMQ + PDT group. Human study also delivered excellent results in both the patients with complete clearance of lesion after 3-6 sessions of treatment.Conclusion: PDT combined with imiquimod may have enhanced effect for the treatment of invasive cSCC. Maximum number of apoptotic cells in IMQ + PDT group can be attributed to increased number of CD8 + T cells in this group. Additional mechanism of enhanced efficacy in IMQ + PDT group may be due to increased expression of markers tested in this study.