Cutaneous squamous cell carcinomas (SCCs) are a major complication of some subtypes of epidermolysis bullosa (EB), with high morbidity and mortality rates and unmet therapeutic needs. The high rate of endogenous mutations and the fibrotic stroma are considered to contribute to the pathogenesis. Patients with dystrophic EB (DEB) and Kindler EB (KEB) have the highest propensity for developing SCCs. Another patient group that develops high-risk SCCs is immunosuppressed (IS) patients, especially after organ transplantation. Herein, we interrogate whether immune checkpoint proteins and immunosuppressive enzymes are dysregulated in EB-associated SCCs as an immune resistance mechanism and compare the expression patterns with those in SCCs from IS patients, who frequently develop high-risk tumors and sporadic SCCs, and immunocompetent (IC) individuals. The expression of indoleamine 2,3-dioxygenase (IDO), programmed cell death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), T cell immunoglobulin and mucin-domain-containing protein-3 (TIM-3), lymphocyte activation gene-3 (LAG-3), and inflammatory infiltrates (CD4, CD8, and CD68) was assessed via immunohistochemistry and semi-quantitative analysis in 30 DEB-SCCs, 22 KEB-SCCs, 106 IS-SCCs, and 100 sporadic IC-SCCs. DEB-SCCs expressed significantly higher levels of IDO and PD-L1 in tumor cells and PD-1 in the tumor microenvironment (TME) compared with SCCs from IC and IS individuals. The number of CD4-positive T cells per mm2was significantly lower in DEB-SCCs compared with IC-SCCs. KEB-SCCs showed the lowest expression of the exhaustion markers TIM-3 and LAG-3 compared with all other groups. These findings identify IDO, PD-1, and PD-L1 to be increased in EB-SCCs and candidate targets for combinatory treatments, especially in DEB-SCCs.
皮肤鳞状细胞癌是大疱性表皮松解症某些亚型的主要并发症，具有高发病率和高死亡率，且治疗需求未得到满足。高内源性突变率和纤维化间质被认为是其发病机制的重要因素。营养不良型大疱性表皮松解症和Kindler型大疱性表皮松解症患者发生鳞状细胞癌的倾向最高。另一类易发生高危鳞状细胞癌的患者群体是免疫抑制患者，特别是在器官移植后。本研究旨在探讨免疫检查点蛋白和免疫抑制酶是否在大疱性表皮松解症相关鳞状细胞癌中失调作为一种免疫抵抗机制，并将其表达模式与常发生高危肿瘤的免疫抑制患者鳞状细胞癌、散发性鳞状细胞癌以及免疫正常个体的鳞状细胞癌进行比较。通过免疫组织化学和半定量分析，评估了30例营养不良型大疱性表皮松解症相关鳞状细胞癌、22例Kindler型大疱性表皮松解症相关鳞状细胞癌、106例免疫抑制患者鳞状细胞癌和100例散发性免疫正常个体鳞状细胞癌中吲哚胺2,3-双加氧酶、程序性细胞死亡蛋白-1、程序性细胞死亡配体-1、T细胞免疫球蛋白和黏蛋白结构域蛋白-3、淋巴细胞活化基因-3以及炎症浸润细胞（CD4、CD8和CD68）的表达。与免疫正常个体和免疫抑制患者的鳞状细胞癌相比，营养不良型大疱性表皮松解症相关鳞状细胞癌在肿瘤细胞中表达显著更高水平的吲哚胺2,3-双加氧酶和程序性细胞死亡配体-1，并在肿瘤微环境中表达更高水平的程序性细胞死亡蛋白-1。与免疫正常个体鳞状细胞癌相比，营养不良型大疱性表皮松解症相关鳞状细胞癌中每平方毫米CD4阳性T细胞数量显著较低。与所有其他组相比，Kindler型大疱性表皮松解症相关鳞状细胞癌中耗竭标志物T细胞免疫球蛋白和黏蛋白结构域蛋白-3及淋巴细胞活化基因-3的表达最低。这些发现表明，吲哚胺2,3-双加氧酶、程序性细胞死亡蛋白-1和程序性细胞死亡配体-1在大疱性表皮松解症相关鳞状细胞癌中表达增加，是联合治疗的潜在靶点，尤其是在营养不良型大疱性表皮松解症相关鳞状细胞癌中。
肿瘤(癌症)患者之家