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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 phosphoeIF4E-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.sup.+] 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.sup.+][PD-1.sup.+][CD8.sup.+] 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., Introduction Malignant melanoma is the deadliest form of skin cancer. In melanoma, the major signaling pathways, RAS/RAF/MAPK and PI3K/AKT, are constitutively activated through numerous avenues, including genetic alterations in BRAF [...]

Simple Summary: Breast cancer (BCa) is a devastating disease, which has a high prevalence and mortality in women. BCa metastasis is a major cause of mortality, and bone metastasis accounts for the majority of BCa-associated deaths. The luminal B subtype of BCa is immunogenically low and has the highest propensity to form bone metastasis compared to other BCa subtypes. Recent efforts have targeted BCa with immune checkpoint inhibitor (CPI) therapy. Although some clinical success in other BCa subtypes, luminal BCas had limited success. This has led to combining immune-stimulating therapies with CPIs to enhance the effectiveness of CPI therapy. We have demonstrated that a natural methyl donor, S-adenosylmethionine (SAM), has significant anti-cancer effects in various cancer models including all subtypes of BCa. Here, we show that SAM in combination with anti-PD-1 antibody has an enhanced anti-cancer efficacy compared to SAM, anti-PD-1 antibody, and control. The combination significantly reduced primary tumor growth and metastasis to lungs and bone. Hence, combining SAM with CPI has the potential to treat luminal B BCa. Breast cancer (BCa) is the most prevalent cancer in females and has a high rate of mortality, especially due to increased metastasis to skeletal and non-skeletal sites. Despite the marked clinical accomplishment of immune checkpoint inhibitor (CPI) therapy in patients with several cancers, it has had limited success in luminal subtypes of BCa. Accordingly, recent efforts have focused on combination therapy with CPI, including epigenetic modulators, to increase response rates of CPI in luminal BCa. We have previously shown that S-adenosylmethionine (SAM), the ubiquitous methyl donor, has strong anti-cancer effects in various cancers, including all subtypes of BCa. In the current study, we took a novel approach and examined the effect of CPI alone and in combination with SAM on tumor growth and metastasis in a syngeneic mouse model of luminal B BCa. We showed that SAM decreases cell proliferation, colony-formation (survival), and invasion of luminal B BCa cell lines (Eo771, R221A) in vitro. In in vivo studies, in Eo771 tumor-bearing mice, either SAM or anti-PD-1 antibody treatment alone significantly reduced tumor growth and progression, while the SAM+anti-PD-1 combination treatment had the highest anti-cancer efficacy of all groups. The SAM+anti-PD-1 combination reduced the percentage of animals with lung metastasis, as well as total metastatic lesion area, compared to control. Additionally, the SAM+anti-PD-1 combination significantly reduced the skeletal lesion area and protected tibial integrity to a greater extent than the monotherapies in an Eo771 bone metastasis model. Transcriptome analysis of Eo771 primary tumors revealed significant downregulation of pro-metastatic genes, including Matrix metalloproteinases (MMPs) and related pathways. On the other hand, CD8+ T cell infiltration, CD8+ T cell cytotoxicity (elevated granzymes), and immunostimulatory genes and pathways were significantly upregulated by the combination treatment. The results presented point to a combination of SAM with CPI as a possible treatment for luminal B BCa that should be tested in clinical studies. [ABSTRACT FROM AUTHOR]