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      Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis

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          Abstract

          Lung cancer is a leading cause of cancer-related deaths worldwide. Lung cancer risk factors, including smoking and exposure to environmental carcinogens, have been linked to chronic inflammation. An integral feature of inflammation is the activation, expansion and infiltration of diverse immune cell types, including CD4 + T cells. Within this T cell subset are immunosuppressive regulatory T (Treg) cells and pro-inflammatory T helper 17 (Th17) cells that act in a fine balance to regulate appropriate adaptive immune responses.

          In the context of lung cancer, evidence suggests that Tregs promote metastasis and metastatic tumor foci development. Additionally, Th17 cells have been shown to be an integral component of the inflammatory milieu in the tumor microenvironment, and potentially involved in promoting distinct lung tumor phenotypes. Studies have shown that the composition of Tregs and Th17 cells are altered in the tumor microenvironment, and that these two CD4 + T cell subsets play active roles in promoting lung cancer progression and metastasis.

          We review current knowledge on the influence of Treg and Th17 cells on lung cancer tumorigenesis, progression, metastasis and prognosis. Furthermore, we discuss the potential biological and clinical implications of the balance among Treg/Th17 cells in the context of the lung tumor microenvironment and highlight the potential prognostic function and relationship to metastasis in lung cancer.

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          A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.

          Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.
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            Inflammation and cancer: advances and new agents.

            Tumour-promoting inflammation is considered one of the enabling characteristics of cancer development. Chronic inflammatory disease increases the risk of some cancers, and strong epidemiological evidence exists that NSAIDs, particularly aspirin, are powerful chemopreventive agents. Tumour microenvironments contain many different inflammatory cells and mediators; targeting these factors in genetic, transplantable and inducible murine models of cancer substantially reduces the development, growth and spread of disease. Thus, this complex network of inflammation offers targets for prevention and treatment of malignant disease. Much potential exists in this area for novel cancer prevention and treatment strategies, although clinical research to support targeting of cancer-related inflammation and innate immunity in patients with advanced-stage cancer remains in its infancy. Following the initial successes of immunotherapies that modulate the adaptive immune system, we assert that inflammation and innate immunity are important targets in patients with cancer on the basis of extensive preclinical and epidemiological data. The adaptive immune response is heavily dependent on innate immunity, therefore, inhibiting some of the tumour-promoting immunosuppressive actions of the innate immune system might enhance the potential of immunotherapies that activate a nascent antitumour response.
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              Lung cancer in never smokers--a different disease.

              Although most lung cancers are a result of smoking, approximately 25% of lung cancer cases worldwide are not attributable to tobacco use, accounting for over 300,000 deaths each year. Striking differences in the epidemiological, clinical and molecular characteristics of lung cancers arising in never smokers versus smokers have been identified, suggesting that they are separate entities. This Review summarizes our current knowledge of this unique and poorly understood disease.
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                Author and article information

                Contributors
                emarshall@bccrc.ca
                kng@bccrc.ca
                +1 604-675-8111 , skung@bccrc.ca
                econway@bccrc.ca
                vmartinez@bccrc.ca
                lhalvorsen@bccrc.ca
                rowbothamdave@gmail.com
                evucic@bccrc.ca
                aplumb@mail.ubc.ca
                dbecker@bccrc.ca
                kenfield@bccrc.ca
                jkennet@bccrc.ca
                kbennewi@bccrc.ca
                wlockwood@bccrc.ca
                slam2@bccancer.bc.ca
                john.english@vch.ca
                ninan@mail.ubc.ca
                +1 604-675-8111 , wanlam@bccrc.ca
                Journal
                Mol Cancer
                Mol. Cancer
                Molecular Cancer
                BioMed Central (London )
                1476-4598
                27 October 2016
                27 October 2016
                2016
                : 15
                : 67
                Affiliations
                [1 ]Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, Canada
                [2 ]Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
                [3 ]Departments of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
                [4 ]Department of Zoology, University of British Columbia, Vancouver, Canada
                [5 ]British Columbia Cancer Research Centre Centre, Vancouver, Canada
                Article
                551
                10.1186/s12943-016-0551-1
                5082389
                27784305
                9361584f-83ef-4481-a12e-594818fd6214
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 14 July 2016
                : 18 October 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;
                Award ID: MOP-123273
                Award ID: MOP-110949
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000521, Canadian Cancer Society;
                Award ID: CCSRI#702535
                Award ID: CCSRI#702520
                Award Recipient :
                Funded by: National Sanitarium Association
                Funded by: FundRef http://dx.doi.org/10.13039/501100004376, Terry Fox Research Institute;
                Categories
                Review
                Custom metadata
                © The Author(s) 2016

                Oncology & Radiotherapy
                th17,il-17,regulatory t cell,treg,lung cancer,inflammation,cancer immunology,tumor microenvironment,tumorigenesis,prognosis

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