Melanoma Laboratory, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Bioinformatics Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Nat Med. 2020 Dec;26(12):1865-1877. doi: 10.1038/s41591-020-1073-3. Epub 2020 Oct 19.
An open question in aggressive cancers such as melanoma is how malignant cells can shift the immune system to pro-tumorigenic functions. Here we identify midkine (MDK) as a melanoma-secreted driver of an inflamed, but immune evasive, microenvironment that defines poor patient prognosis and resistance to immune checkpoint blockade. Mechanistically, MDK was found to control the transcriptome of melanoma cells, allowing for coordinated activation of nuclear factor-κB and downregulation of interferon-associated pathways. The resulting MDK-modulated secretome educated macrophages towards tolerant phenotypes that promoted CD8 T cell dysfunction. In contrast, genetic targeting of MDK sensitized melanoma cells to anti-PD-1/anti-PD-L1 treatment. Emphasizing the translational relevance of these findings, the expression profile of MDK-depleted tumors was enriched in key indicators of a good response to immune checkpoint blockers in independent patient cohorts. Together, these data reveal that MDK acts as an internal modulator of autocrine and paracrine signals that maintain immune suppression in aggressive melanomas.
在侵袭性癌症（如黑色素瘤）中存在一个悬而未决的问题，即恶性细胞如何将免疫系统转变为促进肿瘤发生的功能。在这里，我们发现中期因子（MDK）是黑色素瘤分泌的一种驱动因子，可导致炎症但免疫逃避的微环境，这种微环境定义了患者预后不良和对免疫检查点阻断的耐药性。从机制上讲，MDK 被发现控制着黑色素瘤细胞的转录组，从而协调核因子-κB 的激活和干扰素相关途径的下调。由此产生的 MDK 调节的分泌组将巨噬细胞教育为耐受表型，促进 CD8 T 细胞功能障碍。相比之下，MDK 的基因靶向使黑色素瘤细胞对抗 PD-1/抗 PD-L1 治疗敏感。强调这些发现的转化相关性，在独立的患者队列中，MDK 耗尽肿瘤的表达谱富含对免疫检查点抑制剂良好反应的关键指标。总之，这些数据表明，MDK 作为自分泌和旁分泌信号的内部调节剂，维持侵袭性黑色素瘤中的免疫抑制。
