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      Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity

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          Summary

          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.

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          Highlights

          • Cyclooxygenase in tumors induces PGE 2 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

          Abstract

          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.

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          Most cited references54

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          Hallmarks of Cancer: The Next Generation

          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Immunity, inflammation, and cancer.

            Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and responses to therapy. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. This review outlines the principal mechanisms that govern the effects of inflammation and immunity on tumor development and discusses attractive new targets for cancer therapy and prevention. 2010 Elsevier Inc. All rights reserved.
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              Cancer-related inflammation.

              The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Cell Press
                0092-8674
                1097-4172
                10 September 2015
                10 September 2015
                : 162
                : 6
                : 1257-1270
                Affiliations
                [1 ]Immunobiology Laboratory, The Francis Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
                [2 ]Bioinformatics, The Francis Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
                [3 ]Molecular Oncology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK
                [4 ]Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London WC1E 6DD, UK
                [5 ]Tumor Cell Biology Laboratory, The Francis Crick Institute, Lincoln’s Inn Fields Laboratory, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK
                Author notes
                [∗∗ ]Corresponding author caetano@ 123456crick.ac.uk
                [6]

                Present address: Cancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4BX, UK

                Article
                S0092-8674(15)01028-4
                10.1016/j.cell.2015.08.015
                4597191
                26343581
                aab8223d-db0a-423d-a64f-48a5fe56a9a5
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 October 2014
                : 22 April 2015
                : 16 July 2015
                Categories
                Article

                Cell biology
                Cell biology

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