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

Huang, F.; Goncalves, C.; Bartish, M.; Remy-Sarrazin, J.; Guo, Q.; Emond, A.; Yang, W.; Plourde, D.; Su, J.; Gimeno, M. G.; Zhan, Y.; Attias, M.; Galan, A.; rzymski, T.; Mazan, M.; Masiejczyk, M.; Faber, J.; Khoury, E.; Benoit, A.; Gagnon, N.; Dankort, D.; Piccirillo, C. A.; Journe, F.; Ghanem, G.; Saragovi, H. U.; Sonenberg, N.; Toposiviric, I.; Miller, W. H.; del Rincon, S.

doi:10.1101/2020.05.29.117531

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bioRxiv · 10.1101/2020.05.29.117531

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

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Abstract

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.

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Huang, F., Goncalves, C., Bartish, M., Remy-Sarrazin, J., Guo, Q., Emond, A., Yang, W., Plourde, D., Su, J., Gimeno, M. G., Zhan, Y., Attias, M., Galan, A., rzymski, T., Mazan, M., Masiejczyk, M., Faber, J., Khoury, E., Benoit, A., Gagnon, N., Dankort, D., Piccirillo, C. A., Journe, F., Ghanem, G., Saragovi, H. U., Sonenberg, N., Toposiviric, I., Miller, W. H., del Rincon, S.. 2020-05-30. The MNK1/2-eIF4E axis contributes to phenotype switching, melanoma progression, and resistance to immunotherapy.. https://doi.org/10.1101/2020.05.29.117531

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