Prognostic significance of tumor-infiltrating T cells in ovarian cancer: A meta-analysis
Highlights
► Meta-analysis of ten studies with 1815 ovarian cancer patients confirms a significant survival advantage associated with tumor-infiltrating lymphocytes (TIL). ► This effect was demonstrated across diverse patient cohorts regardless of the tumor grade, stage, or histologic subtype studied. ► A standardized measure of CD8+ TILs in ovarian cancer will facilitate the clinical use of this robust biomarker.
Introduction
Epithelial ovarian cancer is a heterogeneous disease, with significant variation in both the presentation and response to therapy. Prognosis is affected by patient factors, such as age or genetic background, as well as tumor characteristics, including stage, grade, histologic subtype, and chemotherapy sensitivity [1], [2]. Recent studies have also identified immunologic biomarkers of prognosis, with longer survival times documented among women with histologic evidence of an anti-tumor immune response. Although T cells are present in the stroma of most tumor specimens, a survival advantage has been associated specifically with the presence of T cells in epithelial tumor islets (intraepithelial tumor-infiltrating lymphocytes, TILs) [3]. In addition to correlations with clinical outcome, evidence favoring an active role for TILs in tumor clearance is provided by data demonstrating that these are oligoclonal T cell populations that recognize tumor antigens ex vivo and secrete cytokines characteristic of effector cells [[4], [5], [6], [7]]. With the emergence of immunotherapeutic strategies for the treatment of ovarian cancer, it will be important to validate immunologically relevant tumor biomarkers to optimize patient selection for clinical trials and to prospectively track responses to immunotherapeutics [8], [9].
Although all studies of patients with ovarian cancer have described a prognostic advantage associated with intraepithelial TILs, differences in the measurement and characterization of TILs have limited the clinical utility of this biomarker. Questions remain as to whether inconsistencies in results derive from differences in study methodology or whether variable outcomes among diverse patient cohorts illustrate underlying biologic or environmental modifiers of anti-tumor immunity. For example, while some reports have quantified all CD3+ T cells as TILs, others have focused specifically on cytotoxic CD8+ T cells. Additionally, the criteria used to score tumors as TIL-positive or TIL-negative have not been consistent across studies. It is also unclear whether associations between TIL status and survival varied according to the standard prognostic factors, such as age, stage, histology, or surgical outcomes.
The objective of this study is to review the prognostic significance of intraepithelial TILs for overall survival across diverse cohorts of women with ovarian cancer using meta-analytical tools. Our secondary objective is to identify patient, tumor, or methodological characteristics that may explain the variations in the published findings.
Section snippets
Methods
We followed guidelines for the design, analysis, and reporting of meta-analyses of observational studies published by the MOOSE group [10].
Study selection
Of 18 potentially eligible articles, ten met the inclusion criteria and were evaluated further. Fig. 1 provides a summary of the selection process [[3], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]]. The research quality among the selected studies was high; with median quality score of 0.86 (range 0.75 to 0.92).
Patient cohorts
Characteristics of patient cohorts from the analyzed studies are shown in Table 1. The median number of women evaluated per study was 142
Discussion
This meta-analysis confirms that the intraepithelial TILs in ovarian cancer specimens are a robust biomarker for overall survival of women with this disease. This is true in spite of the significant heterogeneity among studies regarding both patient characteristics and scoring methodology. The majority of studies in this meta-analysis used the CD8 marker to specifically evaluate cytotoxic T cells. Although no significant difference was seen in the pooled HRs based on analysis of CD3 or CD8
Conflicts of interest statement
None.
Acknowledgment
This work was supported by the National Cancer Institute Ovarian SPORE grant P01-CA83638.
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- 1
Contributed equally to this work.
- 2
Present Address: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, U.S.A.