背景:尽管免疫疗法彻底改变了晚期皮肤黑色素瘤的治疗方法,仅在少数患者中报告了有效和持久的反应.更好地了解黑色素瘤细胞与微环境的相互作用,包括细胞外基质(ECM)成分,可能提供新的治疗选择。尽管ECM与癌症的几个标志有关,关于ECM蛋白嘌呤-精氨酸-富含和亮氨酸-富含蛋白(PRELP)在癌症中的表达和功能的信息很少,包括黑色素瘤.
方法:结构完整性,PRELP的表达和功能,其与免疫调节分子表达的相关性,使用标准方法和/或生物信息学确定免疫细胞浸润和临床参数.
结果:生物信息学分析显示,但与邻近的正常组织相比,在皮肤皮肤黑色素瘤的可用数据集中,PRELP表达在统计学上显着降低,这与患者生存率降低有关,MHCI类抗原加工机制(APM)和干扰素(IFN)-γ信号转导途径的低表达水平,但转化生长因子(TGF)-β亚型1(TFGB1)和TGF-β受体1(TGFBR1)的表达增加。此外,肿瘤内T细胞的高频率与黑色素瘤病变中MHCI类和PRELP以及T细胞引诱剂CCL5的表达直接相关。在47/49人黑素瘤细胞系分析中发现了边缘到低的PRELP表达水平。由于主要MHCI类APM和IFN-γ途径组分的转录上调,将PRELP转染到黑素瘤细胞系中恢复了I类MHC表面表达。此外,PRELP过表达伴随着细胞上清液中CCL5的高分泌水平,受损的TGF-β信号以及减少的细胞增殖,黑素瘤细胞的迁移和侵袭。
结论:我们的研究结果表明,PRELP诱导黑色素瘤中MHCI类和CCL5的表达,这可能涉及与改善患者预后相关的T细胞募集和免疫原性增强。因此,PRELP可能作为预测疾病进展的标志物,其恢复可以恢复肿瘤的表型,这代表了黑色素瘤的一种新的治疗选择。
Despite immunotherapies having revolutionized the treatment of advanced cutaneous melanoma, effective and durable responses were only reported in a few patients. A better understanding of the interaction of melanoma cells with the microenvironment, including extracellular matrix (ECM) components, might provide novel therapeutic options. Although the ECM has been linked to several hallmarks of cancer, little information is available regarding the expression and function of the ECM protein purine-arginine-rich and leucine-rich protein (PRELP) in cancer, including melanoma.
The structural integrity, expression and function of PRELP, its correlation with the expression of immune modulatory molecules, immune cell infiltration and clinical parameters were determined using standard methods and/or bioinformatics.
Bioinformatics analysis revealed a heterogeneous, but statistically significant reduced PRELP expression in available datasets of skin cutaneous melanoma when compared to adjacent normal tissues, which was associated with reduced patients\' survival, low expression levels of components of the MHC class I antigen processing machinery (APM) and interferon (IFN)-γ signal transduction pathway, but increased expression of the transforming growth factor (TGF)-β isoform 1 (TFGB1) and TGF-β receptor 1 (TGFBR1). In addition, a high frequency of intra-tumoral T cells directly correlated with the expression of MHC class I and PRELP as well as the T cell attractant CCL5 in melanoma lesions. Marginal to low PRELP expression levels were found in the 47/49 human melanoma cell lines analysis. Transfection of PRELP into melanoma cell lines restored MHC class I surface expression due to transcriptional upregulation of major MHC class I APM and IFN-γ pathway components. In addition, PRELP overexpression is accompanied by high CCL5 secretion levels in cell supernatant, an impaired TGF-β signaling as well as a reduced cell proliferation, migration and invasion of melanoma cells.
Our findings suggest that PRELP induces the expression of MHC class I and CCL5 in melanoma, which might be involved in an enhanced T cell recruitment and immunogenicity associated with an improved patients\' outcome. Therefore, PRELP might serve as a marker for predicting disease progression and its recovery could revert the tumorigenic phenotype, which represents a novel therapeutic option for melanoma.