PDF(Pubmed)
Abstract：
Macrophage Migration Inhibitory Factor (MIF) and its homolog D-dopachrome Tautomerase (DDT) have been implicated as drivers of tumor progression across a variety of cancers. Recent evidence suggests MIF as a therapeutic target in immune checkpoint inhibition (ICI) resistant melanomas, however clinical evidence of MIF and particularly of DDT remain limited. This retrospective study analyzed 97 patients treated at Yale for melanoma between 2002-2020. Bulk-RNA sequencing of patient tumor samples from the Skin Cancer SPORE Biorepository was used to evaluate for differential gene expression of MIF, DDT, CD74, and selected inflammatory markers, and gene expression was correlated with patient survival outcomes. Our findings revealed a strong correlation between MIF and DDT levels, with no statistically significant difference across common melanoma mutations and subtypes. Improved survival was associated with lower MIF and DDT levels and higher CD74:MIF and CD74:DDT levels. High CD74:DDT and CD74:MIF levels were also associated with enrichment of infiltrating inflammatory cell markers. These data suggest DDT as a novel target in immune therapy. Dual MIF and DDT blockade may provide synergistic responses in patients with melanoma, irrespective of common mutations, and may overcome ICI resistance. These markers may also provide prognostic value for further biomarker development.
摘要：
巨噬细胞迁移抑制因子(MIF)及其同系物D-多巴色素互变异构酶(DDT)已被认为是多种癌症中肿瘤进展的驱动因素。最近的证据表明MIF作为免疫检查点抑制（ICI）抵抗黑素瘤的治疗靶标，然而,MIF,特别是DDT的临床证据仍然有限.这项回顾性研究分析了2002-2020年间在耶鲁大学接受治疗的97例黑色素瘤患者。来自皮肤癌SPORE生物栓剂的患者肿瘤样品的Bulk-RNA测序用于评估MIF的差异基因表达，滴滴涕,CD74和选定的炎症标志物，基因表达与患者生存结局相关。我们的发现揭示了MIF和DDT水平之间的强相关性，在常见的黑色素瘤突变和亚型之间没有统计学上的显着差异。生存率改善与较低的MIF和DDT水平以及较高的CD74：MIF和CD74：DDT水平相关。高CD74:DDT和CD74:MIF水平也与浸润炎性细胞标志物的富集相关。这些数据表明DDT是免疫治疗的新靶点。双重MIF和DDT阻断可能在黑色素瘤患者中提供协同反应，不管常见的突变，并可以克服ICI抵抗。这些标志物还可以为进一步的生物标志物开发提供预后价值。
