Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity.
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.
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.
Santiago
S
Zelenay
Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Annemarthe G
AG
van der Veen
Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Jan P
JP
Böttcher
Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Kathryn J
KJ
Snelgrove
Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Neil
N
Rogers
Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Sophie E
SE
Acton
Bioinformatics, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Probir
P
Chakravarty
Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Maria Romina
MR
Girotti
Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK.
Richard
R
Marais
Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London WC1E 6DD, UK.
Sergio A
SA
Quezada
Tumor Cell Biology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
Erik
E
Sahai
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.
Caetano
C
Reis e Sousa
D056704:Adaptive Immunity; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015703:Antigens, CD / Q000276:immunology; D001241:Aspirin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007167:Immunotherapy; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D039001:Integrin alpha Chains / Q000276:immunology; D007372:Interferons / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000276:immunology; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D019139:Tumor Escape
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D039001:Integrin alpha Chains; D061026:Programmed Cell Death 1 Receptor; D011453:Prostaglandins; C091367:alpha E integrins; D007372:Interferons; D011451:Prostaglandin-Endoperoxide Synthases; D048493:Proto-Oncogene Proteins B-raf; D001241:Aspirin