Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Melanoma plasticity exhibited as phenotype switching contributes to immunotherapy resistance, however the mechanisms are not completely understood and thus therapeutically unexploited. Here, using a transgenic melanoma mouse model, we demonstrated a critical role of the MNK1/2-eIF4E axis in melanoma plasticity and resistance to immunotherapy. We showed that phospho-eIF4E deficient murine melanomas express high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified that phospho-eIF4E controls the translation of NGFR, a critical effector of phenotype switching. In patients with melanoma, the expression of MKNK1, the kinase for eIF4E, positively correlated with markers of immune exhaustion. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors and increased CD8+ T cell infiltrates. Blocking phospho-eIF4E, using MNK1/2 inhibitors, offers a new strategy to inhibit melanoma plasticity and improve the survival response to anti-PD-1 immunotherapy.

中文翻译：

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MNK1 / 2-eIF4E轴有助于表型转换，黑色素瘤进展和对免疫疗法的抵抗力。

黑色素瘤通常经历从增殖状态到侵入状态的表型转换。黑素瘤可塑性表现为表型转换有助于抵抗免疫治疗，但是其机制尚不完全清楚，因此在治疗上还没有得到利用。在这里，使用转基因黑素瘤小鼠模型，我们证明了MNK1 / 2-eIF4E轴在黑素瘤可塑性和对免疫疗法的抵抗中的关键作用。我们表明，磷酸化-eIF4E缺陷型小鼠黑色素瘤表达高水平的黑素细胞抗原，在患者黑色素瘤中证实了相似的结果。从机理上讲，我们发现磷酸化eIF4E控制着NGFR的翻译，NGFR是表型转换的关键效应子。在黑色素瘤患者中，eIF4E激酶MKNK1的表达与免疫力衰竭的标志物呈正相关。磷酸化eIF4E的遗传消融重新编程了免疫抑制性微环境，例如降低炎症因子的产生和增加CD8 + T细胞浸润。使用MNK1 / 2抑制剂阻断磷酸化eIF4E，提供了一种抑制黑素瘤可塑性并提高对抗PD-1免疫疗法的生存反应的新策略。