The mechanisms by which melanoma and other cancer cells evade anti-tumor immunity remain incompletely understood.,Here, we show that the growth of tumors formed by mutant BrafV600E mouse melanoma cells in an immunocompetent host requires their production of prostaglandin E2, which suppresses immunity and fuels tumor-promoting inflammation.,Genetic ablation of cyclooxygenases (COX) or prostaglandin E synthases in BrafV600E mouse melanoma cells, as well as in NrasG12D melanoma or in breast or colorectal cancer cells, renders them susceptible to immune control and provokes a shift in the tumor inflammatory profile toward classic anti-cancer immune pathways.,This mouse COX-dependent inflammatory signature is remarkably conserved in human cutaneous melanoma biopsies, arguing for COX activity as a driver of immune suppression across species.,Pre-clinical data demonstrate that inhibition of COX synergizes with anti-PD-1 blockade in inducing eradication of tumors, implying that COX inhibitors could be useful adjuvants for immune-based therapies in cancer patients.,•Cyclooxygenase in tumors induces PGE2 that subverts myeloid cell function•COX ablation in tumors enables immune control•COX inhibition synergizes with checkpoint blockade therapy•A COX inflammatory signature is conserved across mouse and human cancer biopsies,Cyclooxygenase in tumors induces PGE2 that subverts myeloid cell function,COX ablation in tumors enables immune control,COX inhibition synergizes with checkpoint blockade therapy,A COX inflammatory signature is conserved across mouse and human cancer biopsies,Cyclooxygenase-driven prostaglandin E2, produced by a variety of tumors, drives malignant growth through successful evasion of type I interferon and/or T-cell-dependent tumor elimination.,A remarkable synergy between cyclooxygenase inhibitors and checkpoint blockade immunotherapy results in tumor eradication.
Resistance to BRAF inhibitors is an emerging problem in the melanoma field.,Strategies to prevent and overcome resistance are urgently required.,The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot.,The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture.,BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling.,Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy.,A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance.,Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.