Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses
Fan Huang, … , Wilson H. Miller Jr., Sonia V. del Rincón
Fan Huang, … , Wilson H. Miller Jr., Sonia V. del Rincón
Published March 9, 2021
Citation Information: J Clin Invest. 2021;131(8):e140752. https://doi.org/10.1172/JCI140752.
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Research Article Oncology

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

Abstract

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.

Authors

Fan Huang, Christophe Gonçalves, Margarita Bartish, Joelle Rémy-Sarrazin, Mark E. Issa, Brendan Cordeiro, Qianyu Guo, Audrey Emond, Mikhael Attias, William Yang, Dany Plourde, Jie Su, Marina Godoy Gimeno, Yao Zhan, Alba Galán, Tomasz Rzymski, Milena Mazan, Magdalena Masiejczyk, Jacek Faber, Elie Khoury, Alexandre Benoit, Natascha Gagnon, David Dankort, Fabrice Journe, Ghanem E. Ghanem, Connie M. Krawczyk, H. Uri Saragovi, Ciriaco A. Piccirillo, Nahum Sonenberg, Ivan Topisirovic, Christopher E. Rudd, Wilson H. Miller Jr., Sonia V. del Rincón

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Figure 5

Phospho-eIF4E deficiency impairs melanoma immunosuppression.

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Phospho-eIF4E deficiency impairs melanoma immunosuppression. (A) Immune ...
(A) Immune cell populations infiltrated into the melanomas from BRafCA/+/Ptenlox/lox eIF4EWT and eIF4EKI mice (day 50). (B) Representative eIF4EWT and eIF4EKI tumor samples (day 50) with IHC staining for granzyme B (left; scale bars: 100 μm) and corresponding scores (right). (C) Schematic of ex vivo experimental designs. (D) Percentage IFN-γ–producing CD8+ cells, stimulated and cultured in the conditioned medium from eIF4EWT or eIF4EKI primary melanoma cultures (WT-CM, KI-CM) or regular medium for 72 hours. (E) MDSC inhibition of IFN-γ production in CD8+ T cells, cultured in WT-CM or KI-CM, relative to corresponding MDSC-free control group. (F–H) MDSC migration toward WT-CM, KI-CM, or regular medium (F); medium containing recombinant murine CCL5 (G); and WT-CM or KI-CM upon maraviroc (MVC; 100 nM) treatment (H). (I) Percent division of CD8+ T cells isolated from the iLNs of eIF4EWT and eIF4EKI tumor-bearing mice, cultured alone or with B16-F10 melanoma cells. One data point was excluded (Grubbs’ test). (J) Percent viability of B16-F10 cells cocultured with T cells from eIF4EWT and eIF4EKI tumor-bearing animals. See also Supplemental Figure 6I. (K) Percent viability of B16-F10 cells, silenced or not for Melan-A (siMlana-1; see Supplemental Table 4), cocultured with T cells from eIF4EWT and eIF4EKI tumor-bearing animals, relative to corresponding control groups. Number of biological replicates (mice) is indicated in each graph. For ex vivo assays (C–K), all tumor-bearing mice were sacrificed between days 35 and 38. (A and B) Two-sided unpaired t test. (D, F, and G) One-way repeated-measures (RM) ANOVA with Tukey’s test. (E and H–K) Two-way RM ANOVA with Šidák correction. All values are represented as mean ± SEM.