Singapore Immunology Network (SIgN), ASTAR, Singapore, Singapore.
J Invest Dermatol. 2011 Sep;131(9):1896-905. doi: 10.1038/jid.2011.128. Epub 2011 Jun 9.
Dacarbazine (DTIC) is the standard first-line drug for advanced stage melanoma, but it induces objective clinical responses in only 15% of patients. This study was designed to identify molecular changes specifically induced by treatment in chemo-sensitive lesions. Using global transcriptome analysis and immunohistochemistry, we analyzed cutaneous metastases resected from patients with melanoma before and after DTIC treatment. The treatment induced similar functional changes in different lesions from the same patient. Stromal and immune response-related genes were the most frequently upregulated, particularly in lesions that responded to treatment by stabilizing or regressing. T-cell infiltration and enhanced major histocompatibility complex class II expression were observed in a subset of patients. Stable, chemo-sensitive lesions exhibited activation of genetic programs related to extracellular matrix remodeling, including increased expression of secreted protein acidic and rich in cysteine (SPARC) by tumor cells. These events were associated with local response to treatment and with superior survival in our group of patients. In contrast, SPARC expression was downregulated in lesions resistant to DTIC. Thus, chemotherapy drugs originally selected for their direct cytotoxicity to tumor cells may also influence disease progression by inducing changes in the tumor microenvironment.
达卡巴嗪（DTIC）是晚期黑色素瘤的标准一线药物，但它仅能诱导 15%的患者出现客观的临床反应。本研究旨在鉴定化疗敏感病变中由治疗特异性诱导的分子变化。我们使用全转录组分析和免疫组织化学技术，分析了黑色素瘤患者在 DTIC 治疗前后切除的皮肤转移灶。治疗在同一患者的不同病变中诱导了相似的功能变化。间质和免疫反应相关基因是最常上调的基因，尤其是在治疗通过稳定或消退而有反应的病变中。在一部分患者中观察到 T 细胞浸润和主要组织相容性复合体 II 表达增强。稳定的、化疗敏感的病变表现出与细胞外基质重塑相关的遗传程序的激活，包括肿瘤细胞中富含半胱氨酸的酸性分泌蛋白（SPARC）的表达增加。这些事件与局部治疗反应以及我们患者群体中的生存优势相关。相比之下，对 DTIC 耐药的病变中 SPARC 的表达下调。因此，最初因其对肿瘤细胞的直接细胞毒性而选择的化疗药物也可能通过诱导肿瘤微环境的变化来影响疾病进展。
