Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses

• Published in: The Journal of clinical investigation Vol. 131; no. 8; pp. 1 - 18
• Main Authors: Huang, Fan, Gonçalves, Christophe, Bartish, Margarita, Rémy-Sarrazin, Joelle, Issa, Mark E., Cordeiro, Brendan, Guo, Qianyu, Emond, Audrey, Attias, Mikhael, Yang, William, Plourde, Dany, Su, Jie, Gimeno, Marina Godoy, Zhan, Yao, Galán, Alba, Rzymski, Tomasz, Mazan, Milena, Masiejczyk, Magdalena, Faber, Jacek, Khoury, Elie, Benoit, Alexandre, Gagnon, Natascha, Dankort, David, Journe, Fabrice, Ghanem, Ghanem E., Krawczyk, Connie M., Saragovi, H. Uri, Piccirillo, Ciriaco A., Sonenberg, Nahum, Topisirovic, Ivan, Rudd, Christopher E., Miller, Wilson H., del Rincón, Sonia V.
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.04.2021
• Subjects: Animal models; Animals; Antigens; Antitumor activity; B7-H1 Antigen - genetics; B7-H1 Antigen - immunology; Biomedical research; Care and treatment; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Dendritic cells; Development and progression; Eukaryotic Initiation Factor-4E - genetics; Eukaryotic Initiation Factor-4E - immunology; Genetic aspects; Genotype & phenotype; Health aspects; Hepatocyte nuclear factor 1; Immune checkpoint; Immune response; Immunity, Cellular; Immunotherapy; Inflammation; Initiation factor eIF-4E; Kinases; Lymphatic system; Lymphocytes T; MAP Kinase Signaling System - genetics; MAP Kinase Signaling System - immunology; Melanoma; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - therapy; Metastasis; Mice; Mice, Transgenic; Microenvironments; Mutation; Nerve growth factor receptors; Patients; PD-1 protein; PD-L1 protein; Phenotype; Phenotypes; Phosphorylation; Phosphotransferases; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - immunology; Receptor, Nerve Growth Factor - genetics; Receptor, Nerve Growth Factor - immunology; Skin cancer; Suppressor cells; Canada; Oncology; Melanoma
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI140752

Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance; however, the mechanisms are not completely understood and thus are therapeutically unexploited. Using melanoma mouse models, we demonstrated that blocking the MNK1/2-eIF4E axis inhibited melanoma phenotype switching and sensitized melanoma to anti-PD-1 immunotherapy. We showed that phospho-eIF4E-deficient murine melanomas expressed high levels of melanocytic antigens, with similar results verified in patient melanomas. Mechanistically, we identified phospho-eIF4E-mediated translational control of NGFR, a critical effector of phenotype switching. Genetic ablation of phospho-eIF4E reprogrammed the immunosuppressive microenvironment, exemplified by lowered production of inflammatory factors, decreased PD-L1 expression on dendritic cells and myeloid-derived suppressor cells, and increased CD8+ T cell infiltrates. Finally, dual blockade of the MNK1/2-eIF4E axis and the PD-1/PD-L1 immune checkpoint demonstrated efficacy in multiple melanoma models regardless of their genomic classification. An increase in the presence of intratumoral stem-like TCF1+PD-1+CD8+ T cells, a characteristic essential for durable antitumor immunity, was detected in mice given a MNK1/2 inhibitor and anti-PD-1 therapy. Using MNK1/2 inhibitors to repress phospho-eIF4E thus offers a strategy to inhibit melanoma plasticity and improve response to anti-PD-1 immunotherapy.