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      The prognostic value of cytotoxic T-lymphocyte antigen 4 in cancers: a systematic review and meta-analysis

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          Abstract

          The outcomes of studies analyzing the prognostic role of CTLA-4 in cancers are controversial. Therefore, the aim of our meta-analysis was to clarify the correlation between CTLA-4 expression and OS in different cancer cases. Relevant literature was searched using PubMed, EMBASE, Web of Science, and the Cochrane Library. The clinicopathological features, hazard ratio (HR) and 95% confidence intervals (CI) were collected from these studies and were analyzed using Stata version 12.0 software. The pooled HR values showed no significant correlation between CTLA-4 expression levels and OS in relation to tumors (HR: 1.24, 95% CI: 0.98–1.56, I2 = 71.7%, P = 0.000). Further subgroup analyses were conducted and categorized by experimental methods, CTLA-4 sources and cancer types. The survey showed a significant correlation (HR: 1.47, 95% CI: 1.14–1.89) between high expression of CTLA-4 and OS in the SNP subgroup, and subgroups analyzing by PCR (HR: 1.50, 95% CI: 1.20–1.86) and flow cytometry (HR: 2.76, 95% CI: 1.49–5.14). In addition, our analysis observed significant differences between patients and controls in inCTLA-4+CD4+ lymphocytes, surCTLA-4+CD4+ lymphocytes, inCTLA-4+CD8+ lymphocytes, and surCTLA-4+CD8+ lymphocytes. Knowledge of the effects of CTLA-4 could potentially be used to effectively guide appropriate prognosis and therapeutic strategies in cancer patients.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Drew M Pardoll (2012)
          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Enhancement of antitumor immunity by CTLA-4 blockade.

            D Leach, M. Krummel, J Allison (1996)
            One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.
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              Language bias in randomised controlled trials published in English and German.

              M. Egger, T Zellweger-Zähner, M. Schneider … (1997)
              Some randomised controlled trials (RCTs) done in German-speaking Europe are published in international English-language journals and others in national German-language journals. We assessed whether authors are more likely to report trials with statistically significant results in English than in German. We studied pairs of RCT reports, matched for first author and time of publication, with one report published in German and the other in English. Pairs were identified from reports round in a manual search of five leading German-language journals and from reports published by the same authors in English found on Medline. Quality of methods and reporting were assessed with two different scales by two investigators who were unaware of authors' identities, affiliations, and other characteristics of trial reports. Main study endpoints were selected by two investigators who were unaware of trial results. Our main outcome was the number of pairs of studies in which the levels of significance (shown by p values) were discordant. 62 eligible pairs of reports were identified but 19 (31%) were excluded because they were duplicate publications. A further three pairs (5%) were excluded because no p values were given. The remaining 40 pairs were analysed. Design characteristics and quality features were similar for reports in both languages. Only 35% of German-language articles, compared with 62% of English-language articles, reported significant (p < 0.05) differences in the main endpoint between study and control groups (p = 0.002 by McNemar's test). Logistic regression showed that the only characteristic that predicted publication in an English-language journal was a significant result. The odds ratio for publication of trials with significant results in English was 3.75 (95% CI 1.25-11.3). Authors were more likely to publish RCTs in an English-language journal if the results were statistically significant. English language bias may, therefore, be introduced in reviews and meta-analyses if they include only trials reported in English. The effort of the Cochrane Collaboration to identify as many controlled trials as possible, through the manual search of many medical journals published in different languages will help to reduce such bias.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Sci Rep
                Journal ID (iso-abbrev): Sci Rep
                Title: Scientific Reports
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2045-2322
                Publication date (Electronic): 17 February 2017
                Publication date Collection: 2017
                Volume: 7
                Electronic Location Identifier: 42913
                Affiliations
                [1 ]Department of Radiation Oncology, Qianfoshan hospital affiliated to Shandong University , 16766 Jingshi Road, Jinan, 250014, P.R. China
                [2 ]Division of Oncology, Department of Graduate, Weifang Medical College , 7166 Baotongxi Road, Weifang, 261053, P.R. China
                Author notes
                [*]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: srep42913
                DOI: 10.1038/srep42913
                PMC ID: 5314410
                PubMed ID: 28211499
                SO-VID: c80b4b91-211b-40c0-b51f-e9275b520928
                Copyright © Copyright © 2017, The Author(s)
                License:

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 17 August 2016
                Date accepted : 17 January 2017
                Categories
                Subject: Article

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