Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 8, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI140752
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Funding
- Canadian Institutes of Health Research (CIHR) [PJT-162260, MOP142281, PJT-156269]
- Canadian Cancer Society [703811]
- Terry Fox Research Institute-Montreal Cancer Consortium (TFRI) [1084]
- Rossy Cancer Network
- National Centre for Research and Development, INNOTECH Program [INNOTECH-K1/HI1/I6/157438/NCBR/12]
- McGill Faculty of Medicine graduate studentships
- Cole Foundation PhD fellowship
- CIHR doctoral fellowship CGS-D
- McGill Integrated Cancer Research Training Program graduate studentships
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By blocking the MNK1/2-eIF4E axis, the study demonstrated inhibition of melanoma phenotype switching and increased sensitivity to anti-PD-1 immunotherapy in melanoma mouse models. Phospho-eIF4E-deficient melanomas expressed high levels of melanocytic antigens, and genetically ablating phospho-eIF4E reprogrammed the immunosuppressive microenvironment. Dual blockade of MNK1/2-eIF4E and PD-1/PD-L1 immune checkpoint showed efficacy in multiple melanoma models and led to an increase in intratumoral stem-like TCF1(+)PD-1(+)CD8(+) T cells.
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.
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