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      The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis

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          Abstract

          Background:

          Tumour-infiltrating lymphocytes (TILs) are often found in tumours, presumably reflecting an immune response against the tumour. We carried out a systematic review and meta-analysis, aiming to establish pooled estimates for survival outcomes based on the presence of TILs in cancer.

          Methods:

          A Pubmed and Embase literature search was designed. Studies were included, in which the prognostic significance of intratumoural CD3+, CD4+, CD8+, and FoxP3+ lymphocytes, as well as ratios between these subsets, were determined in solid tumours.

          Results:

          In pooled analysis, CD3+ TILs had a positive effect on survival with a hazard ratio (HR) of 0.58 (95% confidence interval (CI) 0.43–0.78) for death, as did CD8+ TILs with a HR of 0.71 (95% CI 0.62–0.82). FoxP3+ regulatory TILs were not linked to overall survival, with a HR of 1.19 (95% CI 0.84–1.67). The CD8/FoxP3 ratio produced a more impressive HR (risk of death: HR 0.48, 95% CI 0.34–0.68), but was used in relatively few studies. Sample size and follow-up time seemed to influence study outcomes.

          Conclusion:

          Any future studies should be carefully designed, to prevent overestimating the effect of TILs on prognosis. In this context, ratios between TIL subsets may be more informative.

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          REporting recommendations for tumour MARKer prognostic studies (REMARK)

          L M McShane, D Altman, W Sauerbrei … (2005)
          Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.
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            Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection.

            Qiang Gao, Shuang-Jian Qiu, Jia Fan … (2007)
            To investigate the prognostic value of tumor-infiltrating lymphocytes (TILs), especially regulatory T cells (Tregs), in hepatocellular carcinoma (HCC) patients after resection. CD3+, CD4+, CD8+, Foxp3-positive, and granzyme B-positive TILs were assessed by immunohistochemistry in tissue microarrays containing HCC from 302 patients. Prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff. CD3+, CD4+, CD8+ TILs were associated with neither overall survival (OS) nor disease-free survival (DFS). The presence of low intratumoral Tregs in combination with high intratumoral activated CD8+ cytotoxic cells (CTLs), a balance toward CTLs, was an independent prognostic factor for both improved DFS (P = .001) and OS (P < .0001). Five-year OS and DFS rates were only 24.1% and 19.8% for the group with intratumoral high Tregs and low activated CTLs, compared with 64.0% and 59.4% for the group with intratumoral low Tregs and high activated CTLs, respectively. Either intratumoral Tregs alone (P = .001) or intratumoral activated CTLs (P = .001) alone is also an independent predictor for OS. In addition, high Tregs density was associated with both absence of tumor encapsulation (P = .032) and presence of tumor vascular invasion (P = .031). Tregs are associated with HCC invasiveness, and intratumoral balance of regulatory and cytotoxic T cells is a promising independent predictor for recurrence and survival in HCC. A combination of depletion of Tregs and concomitant stimulation of effector T cells may be an effective immunotherapy to reduce recurrence and prolong survival after surgery.
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              Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions.

              Nobuyoshi Hiraoka, Kaoru Onozato, Tomoo Kosuge … (2006)
              Antitumor immune response changes drastically during the progression of cancers. Established cancers often escape from the host immune system, although specific immune surveillance operates in the early stages of tumorigenesis in murine models. CD4+CD25+ regulatory T cells (TR) play a central role in self-tolerance and suppress effective antitumor immune responses. The aim of this study was to investigate the clinical significance and roles of TR in the progression and multistep carcinogenesis of pancreatic ductal adenocarcinoma. We raised anti-FOXP3 antibodies and used them in immunohistochemical studies of the prevalence of FOXP3+CD4+CD25+ TR in the CD4+ T cells, which infiltrated in tissue and draining lymph nodes of 198 pancreatic ductal adenocarcinomas, their premalignant lesions (84 lesions of pancreatic intraepithelial neoplasias and 51 intraductal papillary-mucinous neoplasms), and 15 nonneoplastic pancreatic lesions. The prevalence of TR was significantly increased in the ductal adenocarcinomas compared with that in the stroma of nonneoplastic inflammation (P<0.0001). The increased prevalence of T(R) was significantly correlated with certain clinicopathologic factors. A better prognosis was observed in patients with a low prevalence of T(R), and this was independent of other survival factors (P<0.0001). Infiltration of intraepithelial CD8+TIA-1+ cytotoxic T cells in pancreatic ducts was marked in low-grade premalignant lesions but diminished during the progression of both pancreatic intraepithelial neoplasias and intraductal papillary-mucinous neoplasms. Conversely, the prevalence of TR increased significantly during the progression of premalignant lesions. T(R) play a role in controlling the immune response against pancreatic ductal carcinoma from the premalignant stage to established cancer. In pancreatic ductal carcinoma, a high prevalence of TR seems to be a marker of poor prognosis.
              Article 0 comments Cited 252 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Br J Cancer
                Title: British Journal of Cancer
                Publisher: Nature Publishing Group
                ISSN (Print): 0007-0920
                ISSN (Electronic): 1532-1827
                Publication date (Print): 28 June 2011
                Publication date (Electronic): 31 May 2011
                Volume: 105
                Issue: 1
                Pages: 93-103
                Affiliations
                [1 ]simpleDepartment of Obstetrics and Gynecology, University Medical Center Groningen, University of Groningen , PO Box 30.001, 9700 RB Groningen, The Netherlands
                [2 ]simpleDepartment of Epidemiology, University Medical Center Groningen, University of Groningen , PO Box 30.001, 9700 RB Groningen, The Netherlands
                [3 ]simpleDepartment of Medical Microbiology, Molecular Virology section, University Medical Center Groningen, University of Groningen , PO Box 30.001, 9700 RB Groningen, The Netherlands
                Author notes
                Article
                Publisher Item ID: bjc2011189
                DOI: 10.1038/bjc.2011.189
                PMC ID: 3137407
                PubMed ID: 21629244
                SO-VID: 5d524b40-6658-41a6-97bd-6ebc6668ffe9
                Copyright © Copyright © 2011 Cancer Research UK
                History
                Date received : 22 December 2010
                Date revision received : 03 May 2011
                Date accepted : 06 May 2011
                Categories
                Subject: Molecular Diagnostics

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: tumour-infiltrating lymphocytes,prognosis,meta-analysis
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: tumour-infiltrating lymphocytes, prognosis, meta-analysis

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