Giurisato et al. developed a mouse model in which extracellular-regulated protein kinase 5 (ERK5) could be selectively ablated in myeloid cells, and demonstrated that ERK5 regulates the JAK/STAT3 pathway to promote tumor-associated macrophage polarization toward the pro-tumor M2 stage, supporting tumor growth and tumor angiogenesis, and protecting tumor cells against chemotherapy. Inhibiting ERK5 reduced the growth of carcinoma grafts in mice and shifted the macrophage population toward the inflammatory M1 state, indicating therapeutic potential.

Owing to the prevalence of tumor-associated macrophages (TAMs) in cancer and their unique influence upon disease progression and malignancy, macrophage-targeted interventions have attracted notable attention in cancer immunotherapy. However, tractable targets to reduce TAM activities remain very few and far between because the signaling mechanisms underpinning protumor macrophage phenotypes are largely unknown. Here, we have investigated the role of the extracellular-regulated protein kinase 5 (ERK5) as a determinant of macrophage polarity. We report that the growth of carcinoma grafts was halted in myeloid ERK5-deficient mice. Coincidentally, targeting ERK5 in macrophages induced a transcriptional switch in favor of proinflammatory mediators. Further molecular analyses demonstrated that activation of the signal transducer and activator of transcription 3 (STAT3) via Tyr705 phosphorylation was impaired in erk5-deleted TAMs. Our study thus suggests that blocking ERK5 constitutes a treatment strategy to reprogram macrophages toward an antitumor state by inhibiting STAT3-induced gene expression.

Author Info: (1) Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy; emanuele.giurisato@manchester.ac.uk cathy.tournier@manchester.ac.uk. Division of Cancer Sciences, School of Medical Sciences, Faculty of

Author Info: (1) Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy; emanuele.giurisato@manchester.ac.uk cathy.tournier@manchester.ac.uk. Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom. (2) Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom. (3) Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25121 Brescia, Italy. (4) Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom. (5) Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom. (6) Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom. (7) Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom. (8) Toxicology Program, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195. (9) Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115. (10) Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115. (11) Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, 25121 Brescia, Italy. Department of Pathology and Immunology, Washington University, St. Louis, MO (12) Toxicology Program, Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195. (13) Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; emanuele.giurisato@manchester.ac.uk cathy.tournier@manchester.ac.uk.

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