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Cell. 2015 Sep 10;162(6):1257-70. doi: 10.1016/j.cell.2015.08.015. Epub 2015 Sep 3.

Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity.

Author information

1
Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. Electronic address: santiago.zelenay@cruk.manchester.ac.uk.
2
Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
3
Bioinformatics, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
4
Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
5
Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London WC1E 6DD, UK.
6
Tumor Cell Biology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
7
Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. Electronic address: caetano@crick.ac.uk.

Abstract

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 Braf(V600E) 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 Braf(V600E) mouse melanoma cells, as well as in Nras(G12D) 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.

PMID:
26343581
PMCID:
PMC4597191
DOI:
10.1016/j.cell.2015.08.015
[Indexed for MEDLINE]
Free PMC Article
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