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Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity

Author:
Zelenay, Santiago, van der Veen, Annemarthe G., Böttcher, Jan P., Snelgrove, Kathryn J., Rogers, Neil, Acton, Sophie E., Chakravarty, Probir, Girotti, Maria Romina, Marais, Richard, Quezada, Sergio A., Sahai, Erik, Reis e Sousa, Caetano
Source:
Cell 2015 v.162 pp. 1257-1270
ISSN:
0092-8674
Subject:
adjuvants, biopsy, colorectal neoplasms, humans, immunity, inflammation, lymphocytes, melanoma, mice, mutants, neoplasm cells, patients, prostaglandin synthase, prostaglandins
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 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.
Agid:
5517333