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      Intratumor Hypoxia Promotes Immune Tolerance by Inducing Regulatory T Cells via TGF-β1 in Gastric Cancer

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          Abstract

          Regulatory T cell (Treg)-mediated immunosuppression represents one of the crucial tumor immune evasion mechanisms and is a main obstacle for successful tumor immunotherapy. Hypoxia, a common feature of solid tumors, has been associated with potentiated immunosuppression, decreased therapeutic response, malignant progression and local invasion. Unfortunately, the link between hypoxia and Treg-mediated immune tolerance in gastric cancer remains poorly understood. In our study, Tregs and hypoxia inducible factor-1α were found to be positively correlated with each other and were increased with the tumor progression. A subsequent in vitro study indicated that supernatants derived from gastric cancer cells under hypoxic condition, could induce the expression of Foxp3 via TGF-β1. These findings confirmed the crucial role of Tregs as a therapeutic target in gastric cancer therapy and provided helpful thoughts for the design of immunotherapy for gastric cancer in the future.

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          Cancer genes and the pathways they control.

          Bert Vogelstein, Kenneth W. Kinzler (2004)
          The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
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            Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells.

            Andrea Facciabene, Xiaohui Peng, Ian S Hagemann … (2011)
            Although immune mechanisms can suppress tumour growth, tumours establish potent, overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (T(reg)) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth. ©2011 Macmillan Publishers Limited. All rights reserved
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              Global cancer statistics in the year 2000.

              D Parkin (2001)
              Estimation of the burden of cancer in terms of incidence, mortality, and prevalence is a first step to appreciating appropriate control measures in a global context. The latest results of such an exercise, based on the most recent available international data, show that there were 10 million new cases, 6 million deaths, and 22 million people living with cancer in 2000. The most common cancers in terms of new cases were lung (1.2 million), breast (1.05 million), colorectal (945,000), stomach (876,000), and liver (564,000). The profile varies greatly in different populations, and the evidence suggests that this variation is mainly a consequence of different lifestyle and environmental factors, which should be amenable to preventive interventions. World population growth and ageing imply a progressive increase in the cancer burden--15 million new cases and 10 million new deaths are expected in 2020, even if current rates remain unchanged.
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                Author and article information

                Contributors
                Nupur Gangopadhyay: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 27 May 2013
                Volume: 8
                Issue: 5
                Electronic Location Identifier: e63777
                Affiliations
                [1 ]Department of Gastroenterology, Second Clinical School of Yangzhou University, Yangzhou, Jiangsu, China
                [2 ]Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
                [3 ]Institute of Integrated Chinese Traditional and Western Medicine, Medical College of Yangzhou University, Yangzhou, Jiangsu, China
                University of Pittsburgh, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: X-ZS PB. Performed the experiments: BD J-MZ YW T-TL. Analyzed the data: BD J-MZ W-MX G-TL. Contributed reagents/materials/analysis tools: W-MX G-TL Y-BD. Wrote the paper: BD J-MZ X-ZS PB.

                Article
                Publisher ID: PONE-D-13-02360
                DOI: 10.1371/journal.pone.0063777
                PMC ID: 3664556
                PubMed ID: 23723999
                SO-VID: fc5e375a-a4db-4b5b-a085-8bb2946d88bc
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 10 January 2013
                Date accepted : 6 April 2013
                Page count
                Pages: 9
                Funding
                This study was supported by the Shanghai Science and Technology Commission (10410709400, 10411950100), National Nature Science Foundation of China (81000968, 81101540, 81101637 and 81172273) and the National Clinical Key Special Subject of China. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Immunology
                Subject: Immune Cells
                Subject: T Cells
                Subject: Immunity
                Subject: Immune Tolerance
                Subject: Medicine
                Subject: Clinical Immunology
                Subject: Immune Cells
                Subject: T Cells
                Subject: Immunity
                Subject: Immune Tolerance
                Subject: Gastroenterology and Hepatology
                Subject: Gastrointestinal Cancers
                Subject: Oncology
                Subject: Basic Cancer Research
                Subject: Tumor Physiology
                Subject: Cancers and Neoplasms
                Subject: Gastrointestinal Tumors
                Subject: Gastric Cancer

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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