The MNK1/2-eIF4E axis contributes to phenotype switching, melanoma progression, and resistance to immunotherapy

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...

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Published inbioRxiv
Main Authors Huang, Fan, Goncalves, Christophe, Bartish, Margarita, Remy-Sarrazin, Joelle, Guo, Qianyu, Emond, Audrey, Yang, William, Plourde, Dany, Su, Jie, Marina Godoy Gimeno, Yao Zhan, Attias, Mikhael, Galan, Alba, Rzymski, Tomasz, Mazan, Milena, Masiejczyk, Magdalena, Faber, Jacek, Khoury, Eli, Benoit, Alexandre, Gagnon, Natascha, Dankort, David, Piccirillo, Ciro A, Journe, Fabrice, Ghanem, Ghanem, Saragovi, Horacio Uri, Sonenberg, Nahum, Toposiviric, Ivan, Miller, Wilson H, Sonia Del Rincon
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 30.05.2020
Subjects
Antigens
CD8 antigen
Genotype & phenotype
Immunotherapy
Inflammation
Initiation factor eIF-4E
Kinases
Lymphocytes T
Melanoma
Nerve growth factor receptors
PD-1 protein
Phenotypes
Phenotypic plasticity
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Summary: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. Competing Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.05.29.117531